Document ID: EPA-HQ-OPP-2008-0121-0005
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2008-04-23T04:00Z

INCIDENT REPORTS ASSOCIATED WITH

Formaldehyde

(methanal, oxomethane, oxymethylene, methylene oxide,

formic aldehyde, methyl aldehyde)

PC Codes: 043001

January 30, 2008

U.S. Environmental Protection Agency

Office of Pesticide Programs

Antimicrobials Division

TABLE OF CONTENTS

  TOC \o "1-3" \h \z \u    HYPERLINK \l "_Toc189673195"  0.0
INTRODUCTION	  PAGEREF _Toc189673195 \h  1  

  HYPERLINK \l "_Toc189673196"  1.0 	INCIDENT REPORT DATA ASSOCIATED
WITH HEALTH EFFECTS	  PAGEREF _Toc189673196 \h  1  

  HYPERLINK \l "_Toc189673197"  1.1	OPP’s Incident Data System (IDS)	 
PAGEREF _Toc189673197 \h  2  

  HYPERLINK \l "_Toc189673198"  1.2	Poison Control Center (1993 –
2003)	  PAGEREF _Toc189673198 \h  2  

  HYPERLINK \l "_Toc189673199"  1.3	California Data - 1982 through 2004	
 PAGEREF _Toc189673199 \h  3  

  HYPERLINK \l "_Toc189673200"  1.4	Incidents and Epidemiological
Studies Published in Scientific Literature	  PAGEREF _Toc189673200 \h  4
 

  HYPERLINK \l "_Toc189673201"  Non-Carcinogenic  - Dermal Exposure	 
PAGEREF _Toc189673201 \h  4  

  HYPERLINK \l "_Toc189673202"  Non-Carcinogenic  - Inhalation Exposure	
 PAGEREF _Toc189673202 \h  5  

  HYPERLINK \l "_Toc189673203"  Non-Carcinogenic  - Oral Exposure	 
PAGEREF _Toc189673203 \h  9  

  HYPERLINK \l "_Toc189673204"  Mutagenic and Carcinogenic Effects	 
PAGEREF _Toc189673204 \h  10  

  HYPERLINK \l "_Toc189673205"  2.0	SUMMARY AND CONCLUSION	  PAGEREF
_Toc189673205 \h  12  

  HYPERLINK \l "_Toc189673206"  3.0	REFERENCES	  PAGEREF _Toc189673206
\h  18  

 

0.0	INTRODUCTION tc \l1 "0.0	INTRODUCTION 

The purpose of this chapter is to review the evidence of health effects
in humans resulting from exposure to formaldehyde.  

Two approaches are used in this section:

The potential health effects of formaldehyde in humans, reported as
incident reports from different sources, are summarized. 

A literature search of health effects associated with formaldehyde
exposure, including results of epidemiological studies, is summarized.

1.0 	INCIDENT REPORT DATA ASSOCIATED WITH HEALTH EFFECTS 

The following databases have been consulted for incident data:

OPP Incident Data System (IDS) - The Incident Data System of The Office
of Pesticide Programs (OPP) of the Environmental Protection Agency (EPA)
contains reports of incidents from various sources, including
registrants, other federal and state health and environmental agencies
and individual consumers, submitted to OPP since 1992.  Reports
submitted to the Incident Data System represent anecdotal reports or
allegations only, unless otherwise stated.  Typically no conclusions can
be drawn implicating the pesticide as a cause of any of the reported
health effects.  Nevertheless, sometimes with enough cases and/or enough
documentation risk mitigation measures may be suggested.

Poison Control Centers - as the result of a data purchase by EPA, OPP
received Poison Control Center data covering the years 1993 through 2003
for all pesticides.  Most of the national Poison Control Centers (PCCs)
participate in a national data collection system, the Toxic Exposure
Surveillance System, which obtains data from about 65-70 centers at
hospitals and universities.  PCCs provide telephone consultation for
individuals and health care providers on suspected poisonings involving
drugs, household products, pesticides, etc.

California Department of Pesticide Regulation - California has collected
uniform data on suspected pesticide poisonings since 1982.  Physicians
are required, by statute, to report to their local health officer all
occurrences of illness suspected of being related to exposure to
pesticides.  The majority of the incidents involve workers.  Information
on exposure (worker activity), type of illness (systemic, eye, skin,
eye/skin and respiratory), likelihood of a causal relationship, and
number of days off work and in the hospital are provided.

Incidents and Epidemiological Studies Published in Scientific Literature
- Some incident reports and/or epidemiological studies associated with
formaldehyde related human health hazards are published in the
scientific literature.

	OPP’s Incident Data System (IDS)

Seven incidents reported for human exposure to formaldehyde occurred in
hospital workers (sterilization of instruments and spill clean-up) and
in persons handling or being in close proximity to pesticide
formulations containing this active ingredient (in combination with
other chemicals).  Five of the 7 incidents reported were solely due to
inhalation of these chemical vapors.  In one incident, where deliberate
and intentional disposal of 9 gallons of formaldehyde (together with
other variable quantities of chemicals) into the school drains exposed
students to several mixtures of chemical vapors.  One of the students
affected was hospitalized due to severe respiratory problems. In a
second incident, the person was exposed to a mixture of chemicals
(formaldehyde, glacial acetic acid and sodium meta-bisulfite) in a
holding tank, next to his work station; and suffered from insomnia,
disorientation, bronchitis, sore throat and severe pain in hands and
feet.  Following a six month period, this person became totally
non-functional. In the third incident, respiratory and gastro-intestinal
tract problems were observed in 17 hospital workers who cleaned up
spills of chemicals containing 4% glutaraldehyde and 3% formaldehyde. 
In the fourth incident, a technician working in proximity to
glutaraldehyde and formaldehyde experienced asthma, arrhythmia,
rhinitis, and was diagnosed as being sensitized to formaldehyde. Similar
effects were observed in the fifth incident of human exposures to
formaldehyde in combination with other chemicals.  

The remaining 2 of 7 incidents occurred via combined routes (inhalation,
dermal and ocular).  A hospital worker exposed to formaldehyde and
glutaraldehyde developed asthma, arrhythmia, airway disease, mucous in
the throat, shortness of breath, rhinitis, dermatitis, eye irritation,
focusing difficulties and symptoms of corneal burn.  In another
incident, a female worker selling industrial/laundry chemicals and
pesticides (chlorinated organophosphorous pesticides, diazinon,
malathion, formaldehyde, methyl ethyl ketone, perchloroethylene, sodium
cyanide, benzene, toluene, vinyl chloride, DDT, chlordane, hepatochlor,
trichloroethene, sodium sulfate, sodium chloride, sodium hypochlorite,
chloroethene, herbicides, volatile organics, acid components, base
neutral compounds and dissolved metals) experienced headaches, mental
confusion, cutaneous T-cell lymphoma, syncopal spells, seizures,
dizziness, loss of equilibrium, nausea, dermatitis, skin irritation and
a rash, that continued for seven years.

The chemical formaldehyde is a known irritant when inhaled and can cause
severe dermal, ocular and gastro-intestinal illnesses.  However, the
human incidents reported for formaldehyde do not reflect exposure to
this chemical alone, but in combination with other chemicals.

1.2	Poison Control Center (1993 – 2003)

There is no one incidence reported in the Poison Control Center Data.

1.3	California Data - 1982 through 2004

There are 116 incidences that have been reported in the California
Pesticide Surveillance Program Database (1982-2004) as definitely or
probably related to formaldehyde alone or in combination. As summarized
in Table 1, symptoms associated with eyes are the primary reported
illness in all the associated incidences.  Nausea, dizziness, headache,
and sore throat are the primary systemic effects that have been
reported. The primary dermal effects that have been reported are rash,
burning sensation, itching, dry scaling irritation, cracking and
thickened skin, itching, and blisters and rash on hands.

As summarized in Table 2, although there are some people who were unable
to work after exposure for a certain period of time, no one was
hospitalized.

Table 1.  Cases Due to Formaldehyde Exposure in California Reported by
Type of Illness and Year, 1982-2004

Year	Illness Type

	Systemic a	Eye	Skin b	Respiratory	Combination c	Total

1982	1	3	-	-	-	4

1983	1	-	-	-	-	1

1984	-	1	1	-	-	2

1985	-	-	1	-	-	1

1986	-	1	-	-	-	1

1987	-	2	-	-	-	2

1988	4	2	-	-	-	6

1989	8	7	1	10	9	17

1990	-	3	-	2	1	4

1991	6	12	1	10	11	18

1992	5	7	2	3	4	13

1993	1	3	-	2	1	5

1994	1	2	-	1	1	3

1995	4	5	1	2	3	9

1996	-	3	2	1	1	5

1997	1	4	3	3	3	8

1998	1	5	2	3	2	9

1999	1	2	-	1	1	3

2001	-	3	-	-	-	3

2002	-	1	-	1	-	2

Total	34	66	14	39	37	116

a 	Category include cases where nausea, sore throat, dizziness, headache
and other systemic effects occurred.

b 	Category includes burning sensation, dry scaling irritation, cracking
and thickened skin, itching, and blisters and rash on hands.

c 	Category includes combined effects to eye, skin,  respiratory and/or
systemic effects.

Table 2. Number of days lost from work or Hospitalized for Indicated
Number of Days after being Exposed to formaldehyde in California,
1982-2004.

	

Number of Days lost from work	

Number of Persons Hospitalized

One day	15	-

Two days	6	-

3-5 days	5	-

6-10 days	-	-

11-16 days	1	-

Indefinite a	1	-

Unknownb	11	-

Note:

(a) An entry of indefinite indicates the event occurred, but the time
period is not known.

(b).An entry of unknown indicates no information was provided.

	Incidents and Epidemiological Studies Published in Scientific
Literature

There are many reported incidents and epidemiological studies been
published in scientific literature.

Non-Carcinogenic  - Dermal Exposure

Formaldehyde is a dermal irritant and a dermal sensitization agent.
Engel and Calnan (1966) reviewed cases of dermatitis noted over three
years (1962-1965) in a car factory among 150 employees who handled
rubber weather strips coated with phenol-formaldehyde resins.  A total
of 50 cases of dermatitis were observed.  The average duration of the
eruption was 12 weeks, however, in three cases it persisted up to 2.5
years.  The eruption was generally an erythematous vesicular rash of the
fingers and hands. Exposure durations were for 1 day to two years before
the onset of the eruption, with an average period of contact of 17
weeks. 29 dermatitis patients were patch-tested.  Among the patch-tested
patients, four (14%) gave a weak reaction to phenol alone, while 65% had
a positive reaction to the adhesive resins.  

Japanese Contact Dermatitis Research Group (1982) summarized patch tests
with 2% formaldehyde (10 mg/cm2) performed at 17 Japanese hospitals on
more than 900 patients and healthy volunteer subjects. Irritation was
noticed in 2.78% and a delayed reaction in 2.62% of the patients.  

One hundred-sixty-seven doctors, 92 dentists, and 333 nurses were
patch-tested with a standard panel of allergens plus allergens common to
their work environment (Rudzki  et al.1989).  Among nurses, formaldehyde
was the disinfectant that most frequently caused allergic reactions
(9.6%). 

Sneddon (1968) monitored 13 staff members for 3 weeks in a haemodialysis
unit where formalin was used as a sterilant.  Patch tests administered
with 3% formalin,  6/13 developed dermatitis, 4 of the 6 were positive
in patch test.

Dermal sensitization is induced only by direct skin contact with
formaldehyde solutions in concentrations higher than 2% (WHO 1989). In
sensitized patients, one of 5 volunteers reacted, under controlled
conditions, to a challenge concentration of 0.01% formaldehyde (Marzulli
and Maibach, 1973).  Occluded patch test study of 20 sensitized subjects
and 20 healthy volunteers (Flyvholm et al. 1977). No skin irritation
occurred in the controls exposed to 1% formaldehyde. In sensitized
subjects, the frequency of response decreased with decreasing
formaldehyde concentrations as follows: 9/20 at 0.5%, 3/20 at 0.1%, 2/20
at 0.05%, and 1/20 at 0.025%.  WHO (1989) concluded that the lowest
patch test challenge concentration in an aqueous solution reported to
produce a reaction in sensitized persons was 0.05%.  

Non-Carcinogenic  - Inhalation Exposure

Formaldehyde has a pungent odor detectable at low concentrations, and
its vapor and solutions are known eye and upper respiratory irritants in
human beings. The common effects of formaldehyde exposure are various
symptoms caused by irritation of the mucosa in the eyes and upper
airways.  

As summarized by NRC (2007), no reports of deaths in humans resulting
from inhaled formaldehyde were mentioned in the literature, and only a
few case reports of accidental inhalation exposures resulting in human
intoxication were found in the reviews consulted (IARC 1995; ATSDR 1999;
ACGIH 2001; Health Canada 2001; WHO 2002; Liteplo and Meek 2003; NAC
2003). Effects of formaldehyde at high but unreported concentrations
include tracheobronchitis and spasms and edema of the larynx (ACGIH
2001). Pulmonary edema, inflammation, and pneumonia occurred after
exposure to airborne formaldehyde at concentrations of 50 to 100 ppm
(ACGIH 2001). 

Exposure to moderate levels of formaldehyde (1-3 ppm) can result in eye
and upper respiratory tract irritation (Weber-Tschoppe et al., 1977;
Kulle et al. 1987).  Feinman (1988) states that most people cannot
tolerate exposures to more than 5 ppm formaldehyde in air; above 10-20
ppm symptoms become severe and shortness of breath occurs. High
concentrations of formaldehyde may result in nasal obstruction,
pulmonary edema, choking, dyspnea, and chest tightness (Porter, 1975;
Solomons and Cochrane 1984).  

Health effects of low-level exposure to formaldehyde is also been
monitored Main and Hogan (1983).  Among 21 subjects exposed to
formaldehyde (0.14 to 1.9 mg/m3) in a mobile home trailer were examined.
 18 unexposed controls were included. No differences in lung function
were found between the two groups.  However, there were significantly
more complaints of eye and throat irritation, headache, and fatigue
among the exposed.  

Allergic reactions and asthma-like conditions also have been reported
following occupational exposures. A medical intern exposure to
formaldehyde over a period of 1 week developed dyspnea, chest tightness,
and edema, following a final 2 hour exposure to high concentrations of
formaldehyde (Porter 1975). Five workers exposed to high concentrations
of formaldehyde from urea-formaldehyde foam insulation experienced
intolerable eye and upper respiratory tract irritation, choking, marked
dyspnea, and nasal obstruction (Solomons and Cochrane, 1984). However,
the concentration of formaldehyde and the contribution of other airborne
chemicals were unknown in both of the reports (OEEHA 1999). 

Asthma has also been suggested in formaldehyde exposed occupational
workers (Burge 1985). Bronchial provocation tests with a mean
formaldehyde concentration of 4.8 mg/m3 (range not given) on 15
formaldehyde-exposed workers with symptoms suggesting occupation-related
asthma.  3 subjects with delayed bronchio-spasm and 6 with an immediate
reduction in forced expiratory volume in one second (FEV1).  

One hundred nine workers and 254 control subjects were studied to
evaluate the effects of formaldehyde on the mucous membranes and lungs.
A modified, respiratory symptom questionnaire and spirometry were admin
to all study participants before and after their work shift, and
formaldehyde levels were determined for each test subject. Over the
course of the monitored work shift, test subjects demonstrated a
dose-dependent excess of irritant symptoms and a statistically
significant decline in certain lung function parameters. Baseline
spirometry values were not significantly different between test and
control groups, and formaldehyde-exposed workers did not report an
excess of respiratory symptoms. Formaldehyde is a dose-dependent
irritant of the eyes & mucous membranes at low-level exposures. It can
exert a small, across-shift effect on airways but after a mean exposure
of 10 yr does not appear to cause permanent respiratory impairment.
(Horvath et. al. 1988)

The effect of formaldehyde exposure on medical students conducting
dissections in the gross anatomy laboratory course was evaluated
(Fleischer 1987).  By using self-administered questionnaires designed to
assess the frequency of occurrence of various symptoms associated with
the acute effects of formaldehyde exposure. The questionnaires were
given to a cohort of 1st-yr medical students on completion of the gross
anatomy lab course. Air sampling of formaldehyde levels in the anatomy
labs was carried out on one day during the time in which these students
were conducting dissections.  Although the results of the air sampling
showed formaldehyde levels to be well below current occupational
standards, significant numbers of students reported experiencing
symptoms associated with formaldehyde exposure. In addition, it was
found that female students were 3 times more likely to report
formaldehyde-related symptoms than male students. 

In a similar study, a group of 24 physical therapy students dissected
cadavers for 3-hour periods per week over 10 weeks.  Estimates of
breathing zone formaldehyde concentrations ranged from 0.49 to 0.93 ppm
(geometric mean 0.73±1.22 ppm).  The peak expiratory flow rate (PEFR),
the only pulmonary function variable measured in this study, was
measured before and after each exposure period. Mean baseline PEFR
declined by about 2%.  Postexposure PEFR means were 1–3% lower than
preexposure PEFR means during the first 4 weeks, but this difference was
not apparent during the last 6 weeks. Fourteen weeks after the end of
the 10-week period, the mean PEFR for the group returned to the
preexposure baseline value (Kriebel et al. 1993).

A prospective evaluation of pulmonary function and respiratory symptoms
among 103 medical students exposed at a TWA concentration that was
generally less than 1 ppm with peak exposures less than 5 ppm was
conducted over a 7-month period.  Acute symptoms of eye and respiratory
irritation were significantly associated with such exposure (Uba et al.
1989).  Formaldehyde exposed workers (<1 mg/m3 with some higher peak
values not stated) in a formaldehyde manufacturing factory . Nasal
symptoms in 30 workers, about 40% of the workers had rhinitis with nasal
obstruction and discharge (Wilhelmsson and Holmstrom, 1987).

38 employees exposed to formaldehyde when working with acid-hardening
lacquers and 18 nonexposed control persons employed at the same company
were examined to determine lung function (spirometry and nitrogen
washout), total immunoglobulin blood concentration, and work-related
symptoms.  The mean exposure to formaldehyde during an 8-hr workday was
0.40 mg/m3 air, and the mean exposure to peak values was 0.70 mg/m3. 
Mean exposure to solvents was low, i.e., approximately 1/10 of the
hygienic effect.   The workers were employed for an average of 7.8
years; estimates of formaldehyde concentrations in workplace air ranged
from 0.2 to 2.1 ppm with a TWA mean of 0.3 ppm.  Eye, nose, and throat
irritation was more common in exposed persons than in controls.  Monday
morning, after two exposure-free days, forced vital capacity (FVC)
values were found to have declined by 0.24 L and forced expiratory
volume in 1 sec (FEV 1) by 0.21 L, compared with normal values
(Alexandersson. and Hedenstierna 1988).

Since January 1978 , the Wisconsin Division of Health has collected air
samples and environmental data on mobile homes, conventional homes, and
offices that have particleboard in their construction and foam
insulation.  The median formaldehyde concentration was 0.47 ppm (range <
0. 1-3.68 ppm) and a positive (inverse) association was present between
age of the structure and formaldehyde concentration. The greatest
prevalence of symptoms was for irritation of mucous membranes, but of
the 256 subjects, 53% reported headaches and 38% reported difficulty in
sleeping.  Among infants and young children, vomiting, diarrhea, and
respiratory problems were identified as particularly important
conditions.  The relationship between smoking and formaldehyde
concentration in the dwelling was examined; smoking did not
significantly increase formaldehyde concentration in the home at the
time of concentration measurement  (Dailly et al., 1981a and 1981b;
Hanrahan  et al. 1981 and 1984).  

On December 1, 1978, a meeting was held in Washington, D.C. to exchange
information dealing with the assessment of potential health problems
associated with formaldehyde emissions following the installation of
urea-formaldehyde foam insulation.  Representatives of eleven states
reported on complaints from residents of a total of 39 homes and
apartments.  At least two atmospheric samples were collected during each
investigation. Shortly after the meeting, the State of Colorado,
Department of Law, Office of the Attorney General issued a warning.  It
stated that, " … urea-formaldehyde foam has characteristics which may
adversely affect health…persons exposed to the substance may
experience any one or all of the following symptoms: Difficulty in
breathing, watery eyes, nasal congestion, ear, nose and throat
irritation, upper respiratory stress, nausea, headache, difficulty in
sleeping, disorientation, skin rashes, dizziness, vomiting, diarrhea,
and asthmatic attacks."  It was noted that 80 percent of the atmospheric
sample results were less than 0.5 ppm formaldehyde  (Wilson, 1987)

Respiratory health of plywood workers occupationally exposed to
formaldehyde is been studied in several epidemiological studies.  93
plywood workers were compared with a group of 93 nonexposed subjects. 
The plywood workers were employed for a mean of 6.2±2.4 years in
workplaces with estimated formaldehyde air concentrations ranging from
0.22 to 3.48 ppm. The mean product of employment duration times
workplace air formaldehyde concentration was 6.2 ppm/year (sd 2.72
ppm/year) for the exposed group of workers; division of this value by
the average duration of employment (6.2 years) arrives at an estimated
average exposure concentration of 1 ppm formaldehyde.  Reported average
respirable and total wood-dust concentrations in workplace air were 0.60
and 1.35 mg/m3, respectively.  The percentages of subjects with abnormal
values for a number of pulmonary function variables (e.g., FEV1 and
FEF25–75) were significantly higher in the group of plywood workers
compared with a group of nonexposed subjects.    Mean values of baseline
FEV1 and FEFR25–75, after adjustment for dust exposure, were
reportedly statistically significantly lower in the exposed group of
workers compared with the nonexposed group (FEV1 2.78 L [sd 0.41] versus
2.82 L [sd 0.3]; and FEF25–75 3.14 L/second [sd 0.76] versus 3.44
L/second [sd 0.78]).  Malaka and Kodama (1990) noted that although the
small differences were statistically significant, their clinical
significance was unclear. 

Biopsy evaluation of the interior turbinate nasal mucosa of 20 men
(average age, 36 years) who had been exposed at 0.1 to 1.1 ppm
formaldehyde during particle board processing for an average of 7 years
(Edling et al. 1985) The histopathological findings were compared to
those from a reference group of 25 men, but who were without
occupational exposure to “irritating agents.”  Five of the
formaldehyde-exposed men had swollen or dry changes, or both, of the
nasal mucosa; microscopic evaluation revealed a loss of cilia and goblet
cells, squamous metaplasia, and, in some individuals, mild dysplasia.  

In a perspective study, Alexandersson, et al (1989) studied the
pulmonary function in wood workers exposed to formaldehyde. Employees
exposed to formaldehyde in the woodworking industry (N = 47) and
nonexposed control subjects (N = 20) were examined in 1980 by spirometry
and the nitrogen washout technique.  A transient impairment of lung
function was noted over a work shift.  Five years later, 21 subjects
were still experiencing exposure to formaldehyde.  A transient decrease
in lung function was again found over a work shift, as evidenced by a
reduction in forced mid-expiratory (FEF25-75) of 0, 15 l/s and an
increase in closing volume (CV%) of 3.0% in nonsmokers.  Significant
decreases in forced expired volume in 1 s as a percent of forced vital
capacity (FEV 1.0/FVC) and FEF25-75 were also noted over the 5 y in
nonsmokers (0.4% and 0, 2 l  s/y, respectively, after correction for
normal aging).  After 4 wk of no exposure (holidays), FEF25-75 and
forced expired vital capacity (FVC, FEV1.0) returned to normal in the
smoking group.  Lung function in workers improved less during the
holiday.  A dose-response relationship was found between exposure to
formaldehyde and decrease in lung function.  Thus, industrial exposure
to formaldehyde causes transient lung function impairment over a work
shift, with a cumulative effect over the years. The impairment, however,
can be reversed with 4 wk of no exposure.

Histological changes in nasal tissue specimens were examined  from a
group of 70 workers in a chemical plant that produced formaldehyde and
formaldehyde resins for impregnation of paper, a group of 100 furniture
factory workers working with particle board and glue components, and a
nonexposed, control group of 36 office workers in the same village as
the furniture factories (Holmstrom et al. 1989) . Mean durations of
employment were 10.4 years for the chemical workers and 9.0 years for
the furniture workers.  Estimates of personal breathing zone air
concentrations ranged from 0.04 to 0.4 ppm for the chemical workers,
from 0.16 to 0.4 ppm for the furniture workers, and from 0.07 to 0.13
ppm in the late summer for the office workers with a year-round office
worker median reported as 0.07 ppm with no standard deviation.  The mean
wood dust concentration in the furniture factory was reported to have
been between 1 and 2 mg/m3.  Nasal histology scores ranged from 0 to 4
for the chemical workers, from 0 to 6 for the furniture workers, and
from 0 to 4 for the office workers.  The mean histological score for the
chemical workers, but not the furniture workers, was significantly
different from the control score, thus supporting the hypothesis that
the development of nasal lesions is formaldehyde-related and not
obligatorily related to a possible interaction between formaldehyde and
wood dust.  The most severe epithelial change (light or moderate
dysplasia) was found in two furniture workers.  Among the control
workers (not exposed to wood dust), loss of cilia, goblet cell
hyperplasia, and cuboidal and squamous cell metaplasia replacing the
columnar epithelium occurred more frequently than in the control group
of office workers.  Within both groups of formaldehyde-exposed workers,
no evidence was found for associations between histological score and
duration of exposure, index of accumulated dose, or smoking habit.  

Horvath et al.  (1988) studied the effects of formaldehyde on the mucous
membranes and lungs in an industrial population. 109 workers and 254
control subjects were studied to evaluate the effects of formaldehyde on
the mucous membranes and lungs.  A modified, respiratory system
questionnaire and spirometry were administered to all study participants
before and after their work shift, and formaldehyde levels were
determined for each test subject.  Estimated TWA formaldehyde
concentrations ranged from 0.17 to 2.93 ppm (mean 0.69 ppm).  Median
concentrations of airborne nuisance particulates (i.e., wood dust) in
the particle board plant were 0.38 and 0.11 mg/m3 for total and
respirable particulates, respectively.  Over the course of the monitored
work shift, test subjects demonstrated a dose-dependent excess of
irritant symptoms and a statistically significant decline in certain
lung function parameters.  Formaldehyde is a dose-depended irritant of
the eyes and mucous membranes at low-level exposures.  It can exert a
small, across-shift effect on airways but after a mean exposure of ten
years does not appear to cause permanent respiratory impairment.

Non-Carcinogenic  - Oral Exposure

Only limited acute cases with oral exposure to formaldehyde have been
published in scientific literature.  Burkhart et al (1990) reported a
case of a 58-year-old man swallowed 4 ounces of formalin (517 mg
formaldehyde/kg) in a suicide attempt. The man was found unconscious by
a co-worker about 1 hour after his shift began. In the emergency room,
the subject regained consciousness but was lethargic. Laboratory results
indicated significant acidosis. Approximately 3 hours after ingesting
the formalin, the patient complained of abdominal pain and began
retching without emesis; he was admitted for observation and treated
with ethanol. The patient's abdominal pains became more severe and he
had difficulty breathing. At 5.5 hours after ingestion, the patient
became obtund, and both his respiratory rate and blood pressure fell
significantly; he was intubated and placed on 100% oxygen.  Shortly
thereafter, the patient began to experience seizures; treatment with
diazepam and phenytoin was unproductive, but pancuronium was effective
in treating the seizures. Intravenous bicarbonate and ethanol therapies
were begun after the seizures started. The patient was transported for
dialysis, but on arrival, had clinical signs of intravascular
coagulopathy. He subsequently sustained a cardiac arrest from which he
could not be revived. At autopsy, the patient’s stomach was hard,
white, and leathery; the esophagus and intestines appeared to be normal.

A 41-year-old woman swallowed 120 mL formalin (37% formaldehyde
solution; 624 mg formaldehyde/kg). The woman was brought to the
emergency room within 30 minutes. The patient complained of abdominal
pain and subsequently lost consciousness.  Upon admission, the patient
was cyanotic, apneic, and hypotensive. Laboratory results indicated
significant acidosis. The patient was intubated, ventilation was
initiated, and gastric lavage was performed. Intravenous fluid therapy
consisting of Ringers solution followed by 5% dextrose, epinephrine, and
sodium bicarbonate was initiated and the patient was transferred to
intensive care. The patient was maintained via endotracheal respiration
and dopamine therapy. The patient became anuric approximately 7.5 hours
after admission, and her health continued to deteriorate over the next
day; she died 28 hours after admission (Eells et al. 1981) 

Kochhar et al (1986) reported a case of a 26-year-old woman ingested 234
mg/kg formaldehyde.  Extensive gastrointestinal damage was exhibited. 
Immediately after ingesting formaldehyde, the patient experienced
repeated vomiting with occasional streaks of blood. Anti-emetics and
antacids were prescribed but did not relieve symptoms. Examination of
the oropharynx revealed ulceration and sloughing of the soft palate and
posterior pharyngeal wall. Indirect laryngoscopy revealed ulceration of
the epiglottis, pyriform fossae, and arytenoids. At 96 hours, an upper
gastrointestinal endoscopy revealed that the esophageal mucosa was
edematous and ulcerated with patches of black slough along the entire
length. Areas of the stomach were hyperemic, and there was superficial
ulceration in the distal body and antrum; the duodenal mucosa appeared
normal. The patient underwent a feeding jejunostomy and made an
uneventful recovery. At 4 weeks, a repeat endoscopy revealed a normal
esophagus. The stomach appeared normal with the exception of slight
hyperemia and limited distensibility of the antrum. Barium examination
revealed scarring of the antrum and distal portion of the gastric body.
At 6 weeks, the patient was asymptomatic.

Mutagenic and Carcinogenic Effects

Formaldehyde has been demonstrated to be genotoxic in a wide variety of
experimental systems both in vitro in animal and human cells and in vivo
in animals (IARC 1995).  As summarized in Table 3, there are some
epidemiological studies associated with potential formaldehyde exposure
with the mutagenic concern of formaldehyde.   

More than forty epidemiological studies have examined the carcinogenic
potential of formaldehyde in animals and humans. The findings from those
studies have been evaluated by a number of agencies and committees
engaged in setting regulatory standards and guidelines (IARC 1995,
2004,, 2006 ; Paustenbach et al. 1997; ATSDR 1999; ACGIH 2001; WHO 2002;
EPA 2003; NAC 2003). 

Some epidemiologic studies (ATSDR 1999) have found an excess number of
nasopharyngeal cancers.  There are two meta-analyses (Blair et al. 1990;
Partanen 1993) reported a relationship between exposure to formaldehyde
and the occurrence of nasopharyngeal cancer was observed, However, those
associations were relatively weak (relative risks [RR] = 2.1 [95%
confidence interval (CI) = 1.1-3.5] and 2.7 [95% CI = 1.4-5.6] in Blair
et al. [1990] and Partanen [1993], respectively). 

In a more recently published meta-analysis (Collins et al. 1997), this
correction for the underreporting was made. In addition, the exposure
potential for the jobs included in the analysis was evaluated. The
authors concluded that the epidemiological studies do not support a
causal relationship between formaldehyde exposure and nasopharyngeal
cancer.  

The follow-up study by Hauptmann et al. (2003, 2004) of the National
Cancer Institute (NCI) retrospective cohort mortality study of U.S.
workers involved in the production or use of formaldehyde represents the
best available data set for quantitative cancer risk assessments of
lymphohematopoietic cancers and nasopharyngeal tumors based on human
data.   The NCI study is a large epidemiology study, and it provides
individual quantitative exposure estimates for the workers.

The analyses conducted by the Agency are based on the
lymphohematopoietic (Hauptmann et al., 2003) and nasopharyngeal
(Hauptmann et al., 2004) cancer results from the NCI follow-up study. 
This is the largest study of the three independent studies, and it is
the only one of the three with sufficient individual exposure data for
exposure-response modeling.  The NCI cohort consisted of 25,619 workers
(88% male) employed in any of the 10 plants prior to 1966; the current
follow-up analyzes 8,486 deaths (178 attributed to lymphohematopoietic
malignancy and 9 to nasopharyngeal cancer).  A detailed exposure
assessment was conducted for each worker based on exposure estimates for
different jobs held and tasks performed (Stewart et al., 1986). 
Exposure estimates were made using several different metrics - peak
exposures, average intensity, cumulative exposure, and duration of
exposure.  Respirator use and exposures to formaldehyde particles and
other chemicals were also considered.  Significant increases in relative
risk for lymphohematopoietic cancer were observed primarily for myeloid
leukemia and Hodgkin’s disease and for the peak exposure and average
intensity exposure metrics.  For the nasopharyngeal cancers, significant
trends were observed for the cumulative and peak exposure metrics.

With respect to the subtypes of lymphohematopoietic malignancy, the
strongest exposure-response relationships were observed for Hodgkin’s
disease and myeloid leukemia for both the peak exposure and average
intensity exposure metrics. The (all) lymphohematopoietic malignancies
category also showed a highly significant trend for the peak exposure
metric and a significant trend with the average intensity metric, and
this was the category selected for the cancer risk analyses presented
here.  While other lymphohematopoietic cancer subtypes did not exhibit
statistically significant increases, many did suggest increases in
relative risk with formaldehyde exposure, and the subtype analyses were
generally based on small numbers of cases (i.e., lower statistical
power).  Furthermore, as noted by the NCI investigators, “although the
accuracy of death certificates for lymphohematopoietic malignancies is
generally high, classification of subtypes of leukemia and lymphoma from
death certificates is less accurate than from hospital records.” 
Finally, the all lymphohematopoietic cancer category contains the most
data, and the results are more stable.

Formaldehyde has been also been demonstrated to be associated with
leukemia in workers. However, the evidence of causing leukemia or other
nonrespiratory cancers in humans has been considered weaker than that
for high-dose formaldehyde exposures to cause nasopharyngeal cancers on
the basis of pharmacokinetic and toxicologic evidence (BEST, 2007)

The Agency’s IRIS program grouped formaldehyde as a B1 (probable human
carcinogen) based on limited evidence in humans, and sufficient evidence
in animals. Human data include nine studies that show statistically
significant associations between site-specific respiratory neoplasms and
exposure to formaldehyde or formaldehyde-containing products. An
increased incidence of nasal squamous cell carcinomas was observed in
long-term inhalation studies in rats and in mice. The classification is
supported by in vitro genotoxicity data and formaldehyde's structural
relationships to other carcinogenic aldehydes such as acetaldehyde. 

SUMMARY AND CONCLUSION 

Although there are many reported incidences been reported associated
with formaldehyde exposure, only limited incidences are associated with
when formaldehyde is used as for antimicrobial agent (biocide). 
Formaldehyde is a dermal irritant and a dermal sensitizer. The primary
dermal effects that have been reported are rash, burning sensation,
itching, dry scaling irritation, cracking and thickened skin, itching,
and blisters and rash on hands.  Acute exposure, symptoms associated
with eyes are the primary reported illness in all the associated
incidences.  Nausea, dizziness, headache, and sore throat are the
primary systemic effects that have been reported.  Allergic reactions
and asthma-like conditions also have been reported following
occupational exposures.  Only limited acute cases with oral exposure to
formaldehyde have been published in scientific literature. Formaldehyde
has been demonstrated to be genotoxic in many reported epidemiological
studies. Formaldehyde exposure has been associated respiratory cancer
(especially nasopharyngeal cancer), leukemia, and other nonrespiratory
cancers in humans.  The Agency’s IRIS program grouped formaldehyde as
a B1 carcinogen. 

Table 3. Human Epidemiological Studies associated Potential Mutagenic
Activity of Formaldehyde Exposure 

Reference Information	Study Design	Results

Ballarin C, Sarto F, Giacomelli L, et al. 1992. Micronucleated cells in
nasal mucosa of formaldehyde-exposed

workers. Mutat Res 280:1-7.	15 nonsmoking workers (8 males, 7 females)
who worked in a plywood factory for cytopathologic changes in nasal
mucosal cells, were evaluated and the results were compared to matched
controls. Mean levels of exposure to formaldehyde ranged from 0.07 to
0.08 ppm in the sawmill and shearing press departments to 0.32 ppm in
the warehouse. The total range of exposure in all areas containing
formaldehyde vapors was 0.06–0.49 ppm. Workers were also exposed to
wood dust. 	Nasal mucosal cells from exposed workers exhibited
significantly increased incidence of micronuclei (0.9 versus 0.25 for
controls), chronic inflammation, and a significantly higher frequency of
squamous metaplasia cells (histological score: 2.3 versus 1.6) than
cells from control workers. Micronuclei were found mainly in the
ciliated cells.

Berke, J.H. (1987): Cytologic Examination of the Nasal Mucosa in
Formaldehyde-Exposed Workers.  J. Occup. Med. 29:681-684.   	Cytologic
study of the nasal mucosa of four groups of employees either engaged in
phenol-formaldehyde impregnation or who were not known to have
experienced regular occupational formaldehyde exposure.  Berke used
historical, environmental occupational hygiene data where formaldehyde
excursions to 9 ppm were documented (with alleged excursions to 15 ppm).
  Smoking habits, measured as pack-years, were very similar for the
exposed and control groups.     	Among formaldehyde-exposed workers with
personal monitoring data, exposures ranged from 0.02 to 2.0 ppm.  A
statistically significant (p=0.04) overall prevalence of nasal erythema,
edema, and fissures among the nonsmokers was found which Berke concluded
was consistent with localized tissue irritation as a consequence of
formaldehyde exposure.  Two people with nasal polyps were confirmed
among the 42 formaldehyde workers, and none were found among the 38
controls.  Berke concluded that there was, however, no significant
association between formaldehyde exposure and “abnormal” nasal
mucosal cytology after simultaneously controlling for age and smoking
habits.  

Chebotarev AN, Titenko NV, Selezneva TG, et al. 1986. Comparison of the
chromosome aberrations,

sister chromatid exchanges, and unscheduled DNA synthesis when
evaluating the mutagenicity of environmental factors. Cytol Genet
20:21-26.	The lymphocytes sister chromatic exchanges (SCEs) of 40
wood-working employees and 22 control workers were examined for
chromosomal aberrations, SCEs, and unscheduled DNA repair or synthesis. 
The level of chromosomal aberrations in formaldehyde-exposed workers was
2.76%, which was significantly elevated compared to spontaneous
chromosomal aberrations in controls (1.64%, p<0.05). The incidence of
chromosomal breakage in exposed workers (2.95%) was significantly
greater than the frequency of spontaneous breakage (1.64%, p<0.05). No
differences between exposed and control subjects were seen for SCEs
either at baseline (8.01 versus 8.24 exchanges per cell) or after
induction with the genotoxin thiotepa (23.32 versus 25.78 exchanges per
cell). There were no differences between formaldehyde-exposed and
control samples in unscheduled DNA repair rates at baseline (335.2
versus 341.9) or after treatment with hydroxyurea (179.8 versus 194.2).
However, when treated with thiotepa, unscheduled DNA repair rates in
lymphocytes from formaldehyde-exposed workers were lower than those from
control workers (217.2 versus 270.4, p<0.05).

Fleig I, Petri N, Stocker WG, et al. 1982. Cytogenetic analyses of blood
lymphocytes of workers exposed to formaldehyde in formaldehyde
manufacturing and processing. J Occup Med 24:1009-1012.	Chromosome
analyses were performed on 15 exposed and 15 non-exposed employees from
formaldehyde manufacturing facilities. Exposed workers had an average
duration of exposure of 28 years (range 23–35 years). Average exposure
concentrations did not exceed 5 ppm prior to 1971 and 1 ppm after 1971.
The formaldehyde exposures of individual workers were classified into
one of the three following categories: Category 1: exposure 25% of
the maximum workplace concentration (MAK); Category 2: exposure up to a
maximum of 60% MAK; and Category 3: exposure up to 100% of the MAK.
Peripheral blood samples were collected from each worker and lymphocytes
were separated and cultured for 70–72 hours at 37 C. Cells were
subsequently fixed and examined for chromatid- and chromosome-type
aberrations. 	There were no differences between exposed and control
groups in the incidence of chromosomal aberrations. The mean frequency
of aberrant metaphases among

formaldehyde-exposed persons was 3.07 versus 3.33% in controls. No
correlation was found between formaldehyde exposure levels and the
number of aberrant metaphases.

Goh  & Cestero (1979) Chromosomal  abnormalities  in

maintenance hemodialysis patients.  J. Med., 10: 167-174.	The
chromosomal patterns of direct  bone

marrow preparations from 40 patients undergoing maintenance
haemo-dialysis were studied.  During the period of this study, each
patient could have received up to 126 ± 50 mg of formaldehyde during
each dialysis.	Aneuploidies, chromosomal structure abnormalities, and
chromosomal breaks were seen in the metaphase.

Shaham J, Bomstein Y, Meltzer A, et al. 1996a. DNA-protein crosslinks, a
biomarker of exposure to formaldehyde - in vitro and in vivo studies.
Carcinogenesis 17:121-125.	The formation of DNA-protein cross links in
peripheral white blood cells of occupationally exposed workers (n=12)
and unexposed controls (n=8) was measured. The average length of
occupational exposure was 13 years. All subjects completed a
questionnaire regarding demographics, occupational and medical
background, and smoking and hygiene habits. Venous blood samples were
collected from each worker and were processed to isolate DNA-protein
cross links. Personal and room concentrations of formaldehyde were
collected at various periods during the working day among the exposed
subjects, with formaldehyde room concentrations ranging from 1.38 to 1.6
ppm. Personal monitoring devices indicated formaldehyde concentrations
of 2.8–3.1 ppm during peak work and an average concentration of 1.46
ppm at times when work was usually completed.	Exposure to formaldehyde
resulted in a significant increase in the incidence of DNA-protein cross
links. Mean (±sd) incidences in exposed and nonexposed workers were
28±6 and 22±6%, respectively. Within the exposed workers group,
technicians had significantly greater levels of DNA-protein cross links
than physicians (32.3±4.3 and 26.3±4.4%, respectively). A linear
relationship between years of exposure and DNA-protein cross links
formation was also detected. When the data were analyzed considering
worker smoking habits, DNA-protein cross links were consistently
elevated among formaldehyde-exposed versus corresponding controls
(p=0.03). The authors concluded that DNA-protein cross links can be used
as a biomarker of exposure; however, the assay measures DNA-protein
cross links in general, not those specific to formaldehyde cross link
formation.

Vasudeva N, Anand C. 1996. Cytogenetic evaluation of medical students
exposed to formaldehyde vapor in the gross anatomy dissection level. J
Am Coll Health 44:177-179.	The effects of formaldehyde exposure on the
incidence of chromosomal aberrations in peripheral blood lymphocytes of
30 medical students exposed to formaldehyde vapors at concentrations of
<1 ppm for 15 months were examined.  Questionnaires established that the
participants were healthy and had insignificant medical histories. 
There was no difference in the incidences of chromosomal aberrations
among the exposed and control groups. The mean frequencies of aberrant
metaphases in the exposed and control groups were 1.2 and 0.9%,
respectively. There was no correlation between reported irritant effects
of formaldehyde and the number of aberrant metaphases, and the authors
concluded that exposure to formaldehyde at concentrations seen in this
study does not lead to chromosomal aberrations.

Yager JW, Cohn KL, Spear RC, et al. 1986. Sister-chromatid exchanges in
lymphocytes of anatomy students exposed to formaldehyde-embalming
solution. Mutat Res 174:135-139.	Peripheral lymphocytes from eight
anatomy students exposed to formaldehyde-embalming solution over a
10-week course were examined for sister chromatid exchange (SCE).
Results were compared with preexposure values for each student. 
Breathing-zone monitoring revealed mean exposure of 1.2 ppm (range
0.73–1.95 ppm). A small average increase in the incidence of SCE was
observed in the lymphocytes of the students after exposure (7.2/cell)
when compared to values obtained before exposure (6.39/cell)

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