See Occupational Exposure Standards
Human Health Effects:
Evidence for Carcinogenicity:
CLASSIFICATION: B1; probable human carcinogen. BASIS FOR CLASSIFICATION:
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.
HUMAN CARCINOGENICITY DATA: Limited. ANIMAL CARCINOGENICITY DATA: Sufficient.
A2. A2= Suspected human carcinogen.
Evaluation: There is limited evidence in humans for the carcinogenicity of
formaldehyde. There is sufficient
evidence in experimental animals for the carcinogenicity of formaldehyde. Overall evaluation: Formaldehyde is probably carcinogenic to
humans (Group 2A).
Human Toxicity Excerpts:
IF SOLN IS INGESTED, MUCOUS MEMBRANES OF MOUTH, THROAT, & INTESTINAL
TRACT ARE IRRITATED, & SEVERE PAIN, VOMITING, & DIARRHEA RESULT. AFTER
ABSORPTION, FORMALDEHYDE DEPRESSES CNS
& SYMPTOMS NOT UNLIKE THOSE OF ALC INTOXICATION ARE NOTED. THEY CONSIST OF
VERTIGO, DEPRESSION, & COMA. RARELY CONVULSIONS ARE OBSERVED.
ALTERATION OF TISSUE PROTEINS BY FORMALDEHYDE CAUSES LOCAL TOXICITY &
PROMOTES ALLERGIC REACTIONS. REPEATED CONTACT WITH SOLN ... MAY CAUSE ECZEMATOID
DERMATITIS. DERMATITIS FROM CLOTHING TREATED WITH FORMALDEHYDE ... HAS OCCURRED.
AQ SOLN ... SPLASHED OR DROPPED ON HUMAN EYES HAVE CAUSED INJURIES RANGING
FROM SEVERE PERMANENT CORNEAL OPACIFICATION & LOSS OF VISION TO MINOR
TRANSIENT INJURY OR DISCOMFORT, DEPENDING UPON WHETHER SOLN WERE OF HIGH OR LOW
CONCN.
INHALATION OF HIGH CONCN ... CAUSED SEVERE IRRITATION OF RESP TRACT, LEADING
IN 2 INSTANCES TO DEATH. ... PULMONARY EDEMA, WITH RESIDUAL CARDIAC IMPAIRMENT
IN 1 CASE, WAS REPORTEDLY CAUSED BY SINGLE ACUTE INHALATIONS ... .
IN SENSITIZED SUBJECTS SPECIFIC LATE ASTHMATIC REACTIONS MAY BE PROVOKED BY
BRIEF EXPOSURES AT APPROX 3 PPM.
Ingestion of formaldehyde can cause a
reduction in body temperature.
Symptoms related to ingestion of formaldehyde include: jaundice, acidosis,
& hematuria. Symptoms related to inhalation include: rhinitis, anosmia,
laryngospasm, tracheitis, & gastroenteritis.
In a survey of 57 embalmers who were exposed to atmospheric concn below 2
ppm, there was a high incidence of symptoms of irritant effects on the eyes
(81%) nose & throat (75%). Other respiratory effects included cough (33%),
chest tightness (23%), wheezing (12%), & shortness of breath (11%). On the
basis of the results, 10% were acute bronchitics, & 30% were chronic
bronchitics. No control group was used & cigarette smoking was not taken
into account.
Eyes: concn 1-10 ppm may produce appreciable eye irritation on initial
exposure; lacrimation occurs at about 4 ppm.
CULTURED BRONCHIAL & FIBROBLASTIC CELLS FROM HUMANS WERE USED TO STUDY
DNA DAMAGE & TOXICITY. FORMATION OF CROSSLINKS BETWEEN DNA & PROTEINS,
CAUSED SINGLE-STRAND BREAKS IN DNA, & INHIBITED RESEALING OF SINGLE-STRAND
BREAKS PRODUCED BY IONIZING RADIATION.
Formaldehyde induced a 1.5-3 fold
increase in sister chromatid exchanges in ... human lymphocytes in culture.
Formaldehyde was mutagenic for
diploid human lymphoblasts in culture ... /inducing an incr number of mutations
at/ 130 uM or 4 ppm by weight.
OUTBREAK OF HEMOLYTIC ANEMIA, ATTRIBUTED TO ACCIDENTAL EXPOSURE ... OCCURRED
AMONG PATIENTS ON HEMODIALYSIS. 41 YR OLD WOMAN DIED 28 HR AFTER INGESTING 120
ML OF ... SOLN (37% WT/VOL FORMALDEHYDE,
12.5% VOL/VOL METHANOL, CONTAINING NO FORMIC ACID).
EFFECTS IN WOMEN ATTRIBUTED TO EXPOSURE ... INCL MENSTRUAL DISORDERS &
SECONDARY STERILITY.
SYMPTOMATOLOGY: A. Inhalation: 1. Irritation of mucous membranes, especially
of eyes, nose & upper respiratory tract. 2. With higher concn, cough,
dysphagia, bronchitis, pneumonia, edema or spasm of the larynx. Pulmonary edema
is uncommon. B. Ingestion. 1. Immediate intense pain in mouth, pharynx &
stomach. 2. Nausea, vomiting, hematemesis, abdominal pain & occasionally
diarrhea (which may be bloody). 3. Pale, clammy skin & other signs of shock.
4. Difficult micturition, hematuria, anuria. 5. Vertigo, convulsions, stupor,
& coma. 6. Death due to respiratory failure. C. Skin contact: 1. Irritation
& hardening of skin. Strong solutions produce coagulation necrosis. 2.
Dermatitis & hypersensitivity from prolonged or repeated exposure.
INVESTIGATIONS OF CILIOSTATIC EFFECT OF ALDEHYDES ARE OF SPECIAL INTEREST
SINCE MANY HAVE IRRITATING EFFECT ON TRACHEAL MUCOSA. COMPARISON OF CILIOSTATIC
EFFECT SHOWED FORMALDEHYDE TO BE MOST
TOXIC FOLLOWED BY ACETALDEHYDE & ACROLEIN. CROTONALDEHYDE & METHACROLEIN
SHOWED WEAKEST EFFECT. TECHNIQUE USED FOR OBSERVING TRACHEAL CILIARY ACTIVITY
WAS THE IN VITRO TECHNIQUE.
One hundred nine workers & 254 control subjects were studied to evaluate
the effects of formaldehyde on the
mucous membranes & lungs. A modified, respiratory symptom questionnaire
& spirometry were admin to all study participants before & after their
work shift, & 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
& a statistically significant decline in certain lung function parameters.
Baseline spirometry values were not significantly different between test &
control groups, & 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.
The effect of formaldehyde exposure
on medical students conducting dissections in the gross anatomy laboratory
course /was evaluated using/ self-administered questionnaires designed to assess
the frequency of occurrence of various symptoms indicating 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. Estimates of the relative risk of experiencing formaldehyde-related symptoms in the anatomy
laboratories compared to the control laboratories ranged from 2.0-19.0,
depending on the particular symptom. In addn, it was found that female students
were 3 times more likely to report formaldehyde-related symptoms than male
students.
A population based case control study was undertaken in 13 counties of
western Washington to determine if occupational formaldehyde exposure was related to cancer of
the oropharynx & hypopharynx (OHPC, N=205), nasopharynx (NPC, N=27) or sinus
& nasal cavity (SNC, N=53). Controls were selected by random digit dialing
(N= 552). A telephone interview inquired about lifetime occupational history as
well as a number of potential confounding factors, including smoking &
drinking. Approximately half (N=143) of the case interviews were with next of
kin. ... Logistic regression was used to estimate exposure odds ratios STET
while taking into account multiple risk factors for each site. No significant
associations were found between occupational formaldehyde exposure & any of the cancer
sites under study. However, relative risk estimates associated with the highest
exposure score categories were evaluated for oropharynx & hypopharynx
(OR=1.3, 95% Confidence Interval= 0.6-3.1) & nasopharynx (OR=2.1, 95%
Cl=0.4-10.0). When an induction period was accounted for only oropharynx &
hypopharynx & nasopharynx increased to 1.7 & 3.1, respectively. Several
limitations in the study tend to conservatively bias the results. ...
Because of the paucity of scientific data concerning the inhalation toxicity
of formaldehyde in humans,
determinations of the symptoms & alterations in pulmonary function resulting
from inhalation for 1 hr of 3 ppm formaldehyde were studied. The protocol
consisted of randomized exposure of each subject to clean air or 3.0 ppm formaldehyde on 2 separate days. Twenty-two
healthy normal subjects engaged in intermittent heavy exercise (VE= 65/min)
& 16 asthmatic subjects performed intermittent moderate exercise (VE=
37/min). Symptoms & pulmonary functions were assessed during the time course
of exposure; nonspecific airway reactivity was assessed after exposure. Both
groups exhibited similar, significant (p<0.01) increases in perceived odor,
nose/throat irritation, & eye irritation throughout the exposure. The
non-asthmatic group had the following slight but statistically significant
(p<0.02) lower pulmonary functions after 55 min of exposure to formaldehyde as compared to clean air: 3.8% in
FEV1, 2.6% in FVC, & 2.8% in FEV3. The asthmatic group showed no
statistically significant decrements in pulmonary function.
A retrospective mortality analysis was conducted in a cohort of 9,365
individuals employed as of 1940 in two chrome leather tanneries in the United
States and followed to the end of 1982. Vital status as of the closing date was
determined for over 95% of the cohort. Potential hazardous workplace exposures
varied with department and included ... formaldehyde. ... Mortality from all causes
combined was lower than expected for each tannery. ... Deaths from cancer of
each site, including the lung, were also lower than expected compared to those
of either the population of the United States or of local state rates. A
significant excess of deaths was observed, however, due to accidental causes in
one tannery and cirrhosis of the liver, suicide, and alcoholism in the other.
These excesses did not appear to be casually associated with occupational
exposures.
Infectivity of human T-cell lymphotropic virus, Type III (HTLV-III) was ...
efficiently inactivated by formalin ...
.
Eight symptomatic individuals chronically exposed to indoor formaldehyde at low concentrations (0.07-0.55
ppm) were compared to 8 nonexposed subjects with respect to: (1) presence of IgG
and IgE antibodies to formaldehyde
conjugated to human serum albumin (F-HSA); (2) the percentage of venous blood T-
and B-cells by E- and EAC-rosetting; and (3) the ability of T- and B-cells to
undergo mitogen (phytohemagglutin and pokeweed) stimulated blastogenesis as
measured by the incorporation of tritiated thymidine. Anti-F-HSA IgG, but not
IgE, antibodies were detected in the sera of the 8 exposed subjects; none were
found in 7 of the controls. T-lymphocytes were decreased in the exposed (48%)
compared to the control (65.9%) subjects (p< 0.01). B-cells were 12.6%
(exposed group) and 14.75% (controls) (p< 0.05). The incorporation of labeled
thymidine by T-cells (phytohemagglutin) was decreased: 17,882 cpm (exposed
group) and 28,576 cpm (p< 0.01). T- and B-cell blastogenesis (pokeweed) was
9,698 cpm (exposed group) and 11,279 (controls) (p< 0.1).
Both death and survival from 4-oz formalin ingestions have been reported in
adults. The probable mean lethal adult dose is 1 to 2 oz. Death may occur within
3 hours; survival past 48 hours usually means recovery.
An environmental survey of 2 wood products (plywood, particle-board)
companies revealed mean concns in the plywood forming areas of 0.8 ppm &, in
2 particle-board forming areas, of 1.1 to 1.4 ppm /formaldehyde/. Ophthalmologic evaluations were
conducted & eye irritation self-reports were collected from 84 subject
workers, including unexposed controls, from various areas in the plants. Results
from both were unremarkable, as were tests mapping their visual fields. However,
there were subjective reports of at least occasional eye irritation in 67% of
the exposed subjects, with more such reports coming from workers in areas of the
plant with the higher concns. An explosion at the factory closed a major product
line & resulted in laying off many of the volunteer subjects prior to
performance testing; the remaining 49 workers were tested before & after
their workshift (& 13 of them were tested on 2 days) in order to assess
acute effects of formaldehyde on visual
acuity, depth perception, peripheral vision, accommodation, eye movement &
fixation, divided attention, & color vision. Subjective reports of eye
irritation on the day of testing did not correlate, or correlated negatively,
with formaldehyde concns on the test
day, which averaged 0.4 ppm. Average visual test scores were better at the end
of the day than at the beginning, & there was a trend for those with higher
formaldehyde levels to demonstrate
greater improvement. Some of the changes reached traditional levels of
statistical significance. The results from this investigation, while relevant to
the neurotoxicity of formaldehyde,
suffer from the small sample size & the possibility that the comparison
subjects had also experienced formaldehyde exposure. With these caveats,
this study suggests that mean formaldehyde exposures at 0.4 ppm produce no
deleterious acute effects on visual performance, but chronic exposures between
0.8 & 1.4 ppm may produce an increased incidence of self reported symptoms
of eye irritation in persons who do not have clinical ophthalmologic defects.
Symptoms: Local: Conjunctivitis, corneal burns; brownish discoloration of
skin; dermatitis, urticaria (hives), pustulovesicular eruption. Inhalation:
rhinitis & anosmia (loss of sense of smell); pharyngitis, laryngospasm;
tracheitis & bronchitis; pulmonary edema, cough, constriction in chest;
dypsnea (difficult breathing), headache, weakness, palpitation (rapid heart
beat), gastro enteritis (inflammation of the stomach & intestines).
Ingestion: Burning in mouth & esophagus; nausea & vomiting; abdominal
pain, diarrhea, vertigo (dizziness), unconsciousness, jaundice, albuminuria,
hematuria, anuria, acidosis, convulsions.
Aldehydes increase airflow at concentrations below those that decrease
respiratory frequency. /Aldehydes/
Data on concentration of formaldehyde
and 15 organic solvents in Finnish furniture factories from 1975 to 1984 were
presented. Workers often complained of severe eye, nose, and upper respiratory
tract irritation. Formaldehyde was
collected in a 1% sodium bisulfite solution and analyzed by the chromatropic
method. The solvents were adsorbed in a charcoal tube, desorbed with
carbon-disulfide or dimethylformamide, and analyzed by gas chromatography. All
highly exposed workers were monitored. The widest range of formaldehyde concentration was recorded in the
operation of the curtain painting furniture receiving operation, which was
between 0.2 and 5.4 ppm. The mean concentrations of most organic solvents
studied ranged from 4 to 66 ppm. Formaldehyde levels were high and the 1 ppm
exposure limit, defined as the 15 minute time weighted average by the Finnish
Board of Labor Protection, was exceeded about 40% of the time.
A study of 759 histologically verified cancers of the nasal cavity (287
cases), paranasal sinuses (179 cases), and nasopharynx (293 cases) and 2465
cancer controls diagnosed in Denmark between 1970 and 1982 was conducted to
investigate the importance of occupational exposure to formaldehyde. Information on job history for
cases and controls was derived from a national data linkage system and exposure
to formaldehyde and wood dust was
assessed by industrial hygienists unaware of the case control status of the
patients. The exposure rates for formaldehyde among male and female controls
were 4.2% and 0.1% respectively. After proper adjustment for contemporary wood
dust exposure, relative risk of 2.3 (95% CI= 0.9-5.8) for squamous cell
carcinoma and 2.2 (95% CI= 7-7.2) for adenocarcinoma of the nasal cavity and
paranasal sinuses were detected among men who have been exposed to formaldehyde in their job compared with those
never exposed.
The National Cancer Institute study on the relationship between exposure to
formaldehyde & mortality from
nasophryngeal cancer was evaluated. The study had indicated little evidence of a
link between formaldehyde at concns
normally encountered in the workplace & risk of nasopharyngeal cancer.
Although the overall standardized mortality ration was significantly elevated in
subjects exposed to formaldehyde, the
overall risk did not incr with increasing intensity of exposure. A reanalysis,
however, suggested that simultaneous exposure to particulates & formaldehyde could be a risk factor. A further
review of the National Cancer Institute findings showed that the significant
excess mortality was based on deaths occurring in a single factory (factory-A)
& occurred primarily in short term employees. When the data were analyzed in
terms of cumulative exposures that were known to include both formaldehyde & particulates, only the
highest exposure group had a significantly increased excess nasopharyngeal
cancer mortality. This excess was clearly located in factory-A. A follow-up
study of factory-A that added 5 more years of follow-up was initiated. It showed
no additional deaths from nasopharyngeal cancer even among workers with the
highest formaldehyde & particulate
exposures. The four deaths from nasopharyngeal cancer in this factory occurred
in workers employed in the same department & hired between 1949 & 1955.
Although these workers were exposed to formaldehyde & particulates, they were not
among the most highly exposed.
This study evaluates the histological changes, especially the presence of
possible precancerous lesions, in the nasal mucosa of workers exposed to formaldehyde. Nasal biopsies of 37 workers
occupationally exposed to formaldehyde
for more than five years and 37 age matched referents showed a higher degree of
metaplastic alterations in the former group. In addition, three cases of
epithelial dysplasia were observed among the exposed. These results indicate
that formaldehyde may be potentially
carcinogenic in man. Combination of this finding with the inconclusive
epidemiological studies suggests that formaldehyde is a weak carcinogen and that
occupational exposure to formaldehyde
alone is insufficient to induce nasal cancer.
Clinical & animal studies suggest that formaldehyde adsorbed on respirable particles
may elicit a greater pulmonary physiologic & inflammatory effect than
gaseous formaldehyde alone. This study
was to determine if respirable carbon particles have a synergistic effect on the
acute symptomatic & pulmonary physiologic response to formaldehyde inhalation. Normal, nonsmoking,
methacholine-nonreactive subjects were exposed to 2 hr each of clean air, 3 ppm
formaldehyde, 0.5 mg/cu m respirable
activated carbon aerosol, & the combination of 3 ppm formaldehyde plus activated carbon aerosol.
The subjects engaged in intermittent heavy exercise (VE= 57 1/min) for 15 min
each half hour. Formaldehyde exposure
was associated with significant increases in reported eye irritation, nasal
irritation, throat irritation, headache, chest discomfort, & odor.
Synergistic increases in cough, but not in other irritant respiratory tract
symptoms, were observed with inhalation of formaldehyde & carbon. Small (<5%)
synergistic decreases in FVC & FEV3 were also seen. No formaldehyde effect was observed on FEV1;
however, we did observe small (<10%) significant decreases in FEF25-75%,
which may be indicative of increased airway tone. Overall, results demonstrated
synergism, but the effect is small & its clinical significance is uncertain.
To study the cytotoxic effect of formaldehyde on the human nasal mucosa 75 men
with occupational exposure to formaldehyde or to formaldehyde & wood dust, were examined,
looking particularly at early signs of irritative effects &
histopathological changes in the nasal mucosa. A nasal biopsy specimen was
graded from 0-8 according to the morphological changes. A high frequency of
nasal symptoms, mostly a running nose & crusting, was related to exposure to
formaldehyde. Only three men had a
normal mucosa; the remainder has loss of cilia & goblet cell hyperplasia
(11%) & squamous metapolasia (78%); in 6 cases (8%) there was a mild
dysplasia. The histological grading showed a significantly higher score when
compared with unexposed controls (2.9 v 1.8). There was no dose response
relation, no malignancies, & no difference in the histological score between
those exposed to formaldehyde or to
formaldehyde & wood dust.
A study of respiratory symptoms and pathophysiological effects associated
with occupational exposure to formaldehyde and wood dust was conducted. The
cohort consisted of 70 Swedish workers exposed to formaldehyde during the production of formaldehyde and formaldehyde based products (formaldehyde group) and 100 furniture workers
exposed to formaldehyde and wood dust
(formaldehyde/wood dust group). The
comparisons consisted of 36 local government clerks. The formaldehyde group was exposed to 0.05 to 0.5
mg/cu m formaldehyde and the furniture
workers to 0.2 to 0.3 mg/cu m formaldehyde and 1 to 2 mg/cu m wood dust.
Annual formaldehyde exposures of the
comparisons averaged 0.09 mg/cu m. Sixty four percent of the formaldehyde group, 53% of the formaldehyde/wood dust group, and 25% of the
comparisons reported nasal discomfort. Symptoms from the lower airways were
reported by 44% of the formaldehyde
group, 39% of the formaldehyde/wood dust
group, and 14 % of the comparisons. Symptoms of nasal obstruction and watery
discharges were more frequent in the exposed subjects than in the comparisons.
More pronounced nasal swelling was found in the cohort than in the comparisons.
20% of the formaldehyde and 15% of the
formaldehyde/wood dust group had
impaired mucociliary clearance versus only 3% of the comparisons. Both exposed
groups had a reduced sense of smell. Forced vital capacity was significantly
decreased in the exposed groups.
A study was conducted to determine if pathologists with exposure to formaldehyde demonstrate an excess risk of
cancer, particularly cancers of the nasopharyngeal and pharyngeal areas. A
population of 6411 physicians with occupational formaldehyde exposure participated in the
study. The occurrence of these types of cancers was 4.7 times higher in these
persons than in a comparable sized group of psychiatrists, but even so it is
difficult to determine the importance of this increased risk as being directly
tied to formaldehyde exposure.
Pathologists and other members of the study group were exposed to other
chemicals and infectious agents as well as formaldehyde. There was an apparent excess of
mortality from pancreatic cancer and brain cancers as well as leukemia.
The relation of chronic respiratory symptoms & pulmonary function to
formaldehyde in homes was studied in a
sample of 298 children (6-15 yr of age) & 613 adults. Formaldehyde measurements were made with
passive samplers during two 1 wk periods. Significantly greater prevalence rates
of asthma & chronic bronchitis were found in children from houses with formaldehyde levels 60-120 ppb than in those
less exposed, especially in children also exposed to environmental tobacco
smoke. In children, levels of peak expiratory flow rates decreased linearly with
formaldehyde exposure, with the
estimated decr due to 60 ppb of formaldehyde equivalent to 22% of peak
expiratory flow rates level in nonexposed children. The effects in asthmatic
children exposed to formaldehyde below
50 ppb were greater than in healthy ones. The effects in adults were less
evident: decrements in peak expiratory flow rates due to formaldehyde over 40 ppb were seen only in the
morning, & mainly in smokers.
The long term effects of formaldehyde
on the respiratory tract have been investigated in a group of 164 workers
exposed daily to the chemical during the production of urea formaldehyde resin, together with 129 workers
not exposed to free formaldehyde.
Exposure was classified as high (corresponding to an 8 hr time weighted exposure
of >2.0 ppm), medium (0.6-2.0 ppm), or low (0.1-0.5 ppm). 25% of workers had
high exposure at some time & 17% moderate exposure. Both exposed &
unexposed groups had an annual assessment that included lung function. The
proportion with self reported respiratory symptoms was similar in the two
groups, 12% & 16% reporting breathlessness on hurrying & 26% & 20%
wheezing. The initial forced expiratory volume in 1 sec was within 0.5 l (approx
on standard deviation) of the predicted value (by age & height) in 65% of
the exposed & 59% of unexposed workers & >0.5 l below the predicted
value in 9% of exposed & 11% unexposed workers. The mean decline in forced
expiratory volume in 1 sec was 42 ml/yr (standard deviation 45) in the exposed
& 41 ml/yr in the unexposed group (standard deviation 40 ml/yr). The rate of
decline showed the expected association with smoking in the unexposed group, but
in the exposed group the mean rate of decline in the never smokers was similar
to that in current smokers. There were, however, relatively few never smokers
& considerable variation in the rates of decline. In the exposed group no
association was found between the rate of decline & indices of exposure to
formaldehyde. Thus there is no evidence
from this study of an excess of respiratory symptoms or decline in lung function
in the workers exposed to formaldehyde.
The similar rate of decline of forced expiratory volume in 1 sec however in
never smokers & smokers of the exposed group is consistent with finding of
other studies for workers exposed to formaldehyde.
A prospective evaluation of pulmonary function & respiratory symptoms was
conducted among 103 medical students exposed to formaldehyde over a 7 month period to
determine the incidence of bronchoconstriction & respiratory symptoms in
response to exposure. Time-weighted average formaldehyde exposures were generally <1
ppm & peak exposures were <5 ppm. Acute symptoms of eye & upper
respiratory irritation were significantly associated with exposure. There was no
pattern of bronchoconstriction in response to exposure after either 2 wks or 7
months. Twelve subjects had a history of asthma; they were likely to have
symptoms of respiratory irritation or changes in pulmonary function than those
without such a history. These findings are consistent with previous case reports
that indicate exposure to formaldehyde
vapor at levels that are commonly encountered in occupational & residential
seetings do not commonly cause significant bronchonconstriction, even among
subjects with preexisting asthma.
A case of anaphylactoid reaction to a patch test with formaldehyde was described. The 40 year old
woman developed bronchospasm and laryngospasm following the inhalation of formaldehyde vapor. A year later she
accidentally entered a hospital room relatively soon after it had been
disinfected, and was hospitalized with dyspnea, cyanosis, bronchospasm, and
laryngospasm. Days later she did react to a patch test with a 1% solution of
formaldehyde in water. Pulmonary
function tests 20 min after the patch test revealed a 50% reduction in FEV1 and
a 63% reduction in MEF 25.
Four groups of patients with long-term inhalation exposure to formaldehyde were compared with controls who
had short-term periodic exposure to formaldehyde. The following were determined
for all groups: total white cell, lymphocyte, and T cell counts; T
helper/suppressor ratios; total Ta1+, IL2+, and B cell counts; antibodies to
formaldehyde-human serum albumin
conjugate and autoantibodies. When compared with the controls, the patients had
significantly higer antibody titers to formaldehyde-human serum albumin. In addition,
significant increases in Ta1+, IL2+, and B cells and autoantibodies were
observed. Immune activation, autoantibodies, and anti formaldehyde-human serum albumin antibodies
are associated with long-term formaldehyde inhalation.
The incidence of spontaneous abortions among hospital staff who used ethylene
oxide, glutaral (glutaraldehyde) & formaldehyde for the chemical sterilization of
instruments was studied using data from a questionnaire & a hospital
discharge register. ... When the staff were concerned in sterilizing during
their pregnancy the frequency was 16.7% compared with 5.6% for the nonexposed
pregnancies. The incr frequency ... correlated with exposure to ethylene oxide
but not with exposure to glutaral or formaldehyde.
Employees exposed to formaldehyde in
the woodworking industry and nonexposed control subjects were examined by
spirometry and the nitrogen washout technique. A dose-response relationship was
found between exposure to formaldehyde
and decrease in lung function. 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.
The mortality of 1,332 male workers employed at least 30 days in 1959-1980 in
a resins-manufacturing plant was examined. Ambient measurements taken in the
plant between 1974 and 1979 documented a potential for exposure to levels of
formaldehyde as high or greater than 3.0
mg/cu m. Vital status was ascertained for 98.6% of the cohort members, and their
mortality was compared with expected deaths drawn from the national and local
population rates. A statistically significant increase in lung cancer was
observed, based on 18 deaths, which was not fully accounted for by possible
confounding factors linked to personal habits or sociocultural characteristics.
This elevated risk, however, could not be attributed specifically to exposure to
formaldehyde. Mortality from digestive
cancer (14 deaths observed) and hematologic neoplasms (5 deaths observed) was
not substantially higher than expected.
Formaldehyde has been found to cause
bronchial asthma-like symptoms in humans. A young male neurology resident who
spent 2 hr in autopsy of formaldehyde-preserved human brains
experienced both conjunctival & nasal irritation while working; however,
over the next 15 hr after cessation of exposure, he developed progressive
dyspnea & tightness in the chest. Early edema indicative of pneumonitis was
visible on Xray, & after treatment with aminophyline, hydrocortisone, &
oxygen (nasal prong at 4 l/min), he gradually improved over the following 2
days. He continued to need prednisone (20 mg every other day for 2 wk), & he
had fully recovered 5 wk after the onset of his hypersensitivity reaction to
inhaled formaldehyde.
In cultured human bronchial fibroblasts exposed to the carcinogen
N-methyl-N-nitrosourea (NMU) in combination with formaldehyde, formaldehyde was observed to inhibit repair of
alkylation of DNA at the O6 guanine position induced by NMU. Whether formaldehyde enhances the effects of other
DNA-damaging agents has not yet been evaluated.
Hemodialysis patients are exposed chronically to trace levels of formaldehyde (by formalin sterilization of their dialyzers to
permit reuse). Erythrocytes can be characterized in terms of MN phenotypes,
analogous to the AB-O system. The normal distribution of MM, NN, an MN
phenotypes is about 25, 25, and 50%, respectively. Only 25% of the population
would be expected to have anti-N antibodies. Formaldehyde exposure may be followed by the
development of anti-N-like antibodies probably as a result of reaction with the
dissolved form of formaldehyde,
methylene glycol. The anti-N-like antibodies are also found following exposure
to sodium hypochlorite.
The use of formaldehyde as a nail
hardener, on the other hand, is accompanied by a significant number of serious
injuries to sensitive nail and adnexal tissues. This type of exposure may
contribute substantially to that portion of the 4% sensitization index seen in
clinical patients which is cosmetic-related.
In a study ..., a group of 33 observers judged the perceived irritation &
odor of formaldehyde during 29-min
chamber esposures to concns ranging from 0.3-2.4 mg/cu m. The sensory irritation
increased with time for the lower concns & decreased with time for the
highest. This effect was true for irritation of eyes, nose, & throat &
the sensitivity proved to be roughly equal for all three sites. The sensory
irritant effect of formaldehyde at 1.2
mg/cu m was shown to decr when the chemical pyridine was injected into the
chanber; such sensory interactions occur in environmentally realistic
situations.
... Healthy volunteers (24 men, 9 women) /were exposed/ to formaldehyde concns ranging between 0.036
& 4.8 mg/cu m air (33 volunteers for 35 min, 48 volunteers for 1.5 min. Eye
blinking rates as well as subjective irritation effects were determined. The
irritation threshold was found to range between 1.2 & 2.4 mg formaldehyde/cu m. A similar threshold (1
mg/cu m) was found in other studies. ... /It was/ noted that 9 out of 53 medical
student volunteers exposed to formaldehyde concns of between 0.39 & 0.60
mg/cu m for 8 hr/wk, complained of headaches, a burning sensation in the eyes,
sore throat, & annoyance because of the smell.
A 60-yr old man swallowed 60-90 mg of a 40% formaldehyde soln. Thirty hr after death, the
mucosa of the lowere part of the esophagus, stomach, & first portion of
duodenum were dark chocolate brown in color & of the consistency of leather.
All organs & tissues in contact with the stomach were "hardened" to a depth
of about 8 mm.
Workers exposed to 0.35-1.0 ppm (0.43-1.2 mg/cu m) for 6 minutes had a
significant irritation response at 1.0 ppm; nonsignificant responses were
reported at 0.7 and 0.9 ppm(0.9 and 1.1 mg/cu m).
Formaldehyde vapor is very irritating
to the mucous membranes and toxic to animals, including man.
... examined smears of nasal respiratory mucosa cells sampled from the inner
turbinate of 15 nonsmokers who were exposed to formaldehyde released from a urea-formaldehyde glue used in a plywood factory
and 15 age- and sex-matched nonexposed clerks from outside of the factory.
Estimates of formaldehyde air conc
ranged from : 0.21 to 0.60 (mean 0.39 + or - 0.20 ppm) in the warehouse where
seven subject worked, 0.08 to 0.14 ppm (mean 0.1 + or - 0.02 ppm) in the
shearing press where six subjects worked, and 0.09 ppm (only one sample taken)
in the sawmill area where two subjects worked. Mean wood dust concn for the
three areas were 0.23 + or - 0.1 mg/m3, 0.41 + or - 0.21 mg/m3, and 0.73 mg/m3,
respectively. Exposed subjects worked at the factory for 2-19 yr (mean 6.8 + or
- 5.0 yr). Nasal mucosal slides were scored as follows: normal cellularity, 1;
number of mucus-secreting cells greater than ciliated cells, 1.5; hyperplasia,
2; squamous metaplasia, 2.5; mild dysplasia, 3; moderate dysplasia, 4; severe
dysplasia, 5; and malignant cells, 6. In the exposed group, all subjects had a
greater number of nonciliated than ciliated cells, 40% had hyperplasia, 67% had
squamous metaplasia, and 6% slight dysplasia. In controls, 26% had normal
cytology, 67% had more ciliated than nonciliated cells, 33% had hyperplasia, and
6% had squamous metaplasia. The mean cytology score for the exposed group (2.3 +
or - 0.5) was reported to be statistically significantly greater than the
control score (1.6 + or - 0.5). Also found in this study was a statistically
significantly higher percentage of micronucleated mucosal cells in the exposed
group compared with the control group (0.91% + or - 0.47 versus 0.25% + or -
0.22).
Mean baseline PEFR /(peak expiratory flow rate)/ declined by about 2% over a
10-wk period in a group of 24 physical therapy students who dissected cadavers
for 3-hr periods/wk ... . Estimates of breathing zone formaldehyde concn ranged from 0.49-0.93 ppm
(geometric mean 0.72 + or - 1.22 ppm). PEFR, the only pulmonary function
variable measured in this study, was measured before & after each exposure
period. Postexposure PEFR means were 1-3% lower than preexposure PEFR means
during the first 4 wk, but this difference was not apparent during the last 6
wk. Fourteen wk after the end of the 10-wk period, the mean PEFR for the group
returned to the preexposure baseline value.
... evaluated the immunologic response of asthmatic subjects exposed to
urea-formaldehyde foam insulation (UFFI)
off-gas products. Subjects consisted of 23 individuals with a history of
asthmatic symptoms attributed to UFFI & 4 individuals (controls) with asthma
unrelated to UFFI by-products. Subjects were exposed to one of the following:
room air (placebo) for 30 min; 1 ppm formaldehyde gas for 3 hr; UFFI particles (4
um, 0.5 particles/ml) for 3 hr, commencing 48 hr after formaldehyde gas exposure; & UFFI off-gas
products for 3 hr, commencing 48 hr after UFFI particle exposure. There were no
significant alterations in any of the white blood cell populations ... .
However, there was a significant incr in the % & absolute number of
eosinophils & basophils in the subject (who also lived in UFFI-homes) after
exposure to UFFI in the exposure chamber when compared to the white blood cell
values obtained before chamber exposure to UFFI.
Occupational exposures to formaldehyde have been assoc with dermal
irritation and the diagnosis of allergic contact dermatitis by patch testing.
Reported historical percentages of subjects with skin problems showing positive
responses to formaldehyde in patch tests
performed by dermatologists using aqueous soln with 1 or 2% formaldehyde incl 7.8% in North America
between 1992 and 1994 ... 1.6% in a 1983-1984 Swedish study ... 2.6% in a
1988-1989 European study ... and 3.7% in a 1990-1994 Polish study ... . Lack of
case-specific exposure info for these patients precludes the determination of
the degree to which sensitization may have been caused by direct dermal contact
to formaldehyde in liquids or by contact
with formaldehyde gas in air, but the
widespread use of formaldehyde or formaldehyde-releasing chemicals in cosmetics
and cleaning agents ... suggest that the dermal route of exposure may be the
more important sensitizing route.
... measured elevated levels of formaldehyde-specific IgE in 24/62 8-yr old
children who were students in three particle board-paneled classrooms with est
formaldehyde air concn of 0.075, 0.069,
and 0.043 ppm. In a health survey, the children reported headaches (29/62),
fatigue (21/62), dry nasal mucosa (9/62), rhinitis (23/62) cough (15/62), and
nosebleeds (14/62). Sums of numbers of children with each of nine symptoms for
each classroom decr with decr formaldehyde conc (49, 47, and 24,
respectively for the 0.075-, 0.069-, and 0.043-ppm classrooms), but the
investigators reported that elevated levels of specific IgE did not correlate
with the number and severity of symptoms. The children were moved to a new
school without particle board paneling and were evaluated again, 3 mo after
moving. Est formaldehyde concn in the
new classrooms were 0.029, 0.023, and 0.026 ppm. The numbers of children
reporting symptoms decr significantly compared with premoving reporting figures,
and mean serum levels of formaldehyde-specific IgE, measured in 20 of
the children, declined significantly compared with premoving mean levels.
... investigated the correlation between formaldehyde-induced contact dermatitis and
granulocyte chemiluminescence resulting from free-radical release in healthy and
formaldehyde-sensitive patients.
Thirteen patients with contact dermatitis who were occupationally exposed to
formaldehyde and five healthy volunteers
participated in the study. All subjects underwent skin-prick tests for common
allergens as well as a histamine inhalation provocation test. Subjects were
exposed to 0.5 mg/m3 (0.41 ppm) formaldehyde for 2 hr, and peak expiratory
flow was measured immediately before exposure, at 60 and 120 min of exposure,
and at 6 and 21 hr after completion of exposure. In formaldehyde-sensitive patients, skin-prick
tests and total serum IgE were normal; no antiformaldehyde IgE was detected. In
formaldehyde-sensitive patients,
peripheral blood granulocyte chemiluminescence significantly incr within 30 min
of exposure commencement, and remained elevated 24 hr later, compared to initial
values. Granulocyte chemiluminescence did not incr in healthy patients.
... measured the formation of DNA-protein cross links in peripheral white
blood cells of occupationally exposed workers (n=12) & unexposed controls
(n=8). The avg length of ... exposure was 13 yr. ... Venous blood samples were
collected ... . Personal & room concn of formaldehyde were collected at various periods
during the working day among the exposed subjects, with formaldehyde room concn ranging from 1.38-1.6
ppm. Personal monitoring devices indicated formaldehyde concn of 2.8-3.1 ppm during peak
work & an avg concn of 1.46 ppm at times when work was usually completed.
Exposure to formaldehyde resulted in a
significant incr in the incidence of DNA-protein cross links. Mean ...
incidences in exposed & nonexposed workers were 28 + or - 6 & 22 + or -
6%, respectively. Within the exposed workers group, technicians had
significantly greater levels of DNA-protein cross links than physicians (32.3 +
or - 4.3 & 26.3 + or - 4.4%, respectively). A linear relationship between yr
of exposure & DNA-protein cross links formation was also detected. When the
data were analyzed considering worker smoking habits, DNA-protein cross links
was consistently elevated among formaldehyde-exposed versus corresponding
controls (p=0.03).
The finding of nasal tumors in rodents exposed to high levels of airborne
formaldehyde in the early 1980s ... led
to a concern for cancer effect in occupationally exposed workers. There are now
more than 40 epidemiology studies examining the potential for occupational formaldehyde exposure to cause cancer in
humans. The studies include cohort mortality studies of formaldehyde-exposed industrial workers,
cohort mortality studies of formaldehyde-exposed professionals or medical
specialists, & case-control studies that looked for assoc between
occupational exposure to formaldehyde
& cancers of the nose, pharynx, or lung. ... Although some of the
epidemiological studies have found some scattered evidence for extra-respiratory
site cancers in groups of formaldehyde-exposed workers, the data are not
consistent across studies & adjustment for potential confounding cancer risk
factors has not often been possible. Most, if not all reviewers, have agreed
that cancer of the respiratory tract, particularly the upper respiratory tract,
is more biologically plausible than formaldehyde-induced cancer at distant sites
given the reactivity of formaldehyde,
the capacity of tissues to metabolize formaldehyde, & the results from chronic
rodent inhalation studies showing that formaldehyde-induced nonneoplastic &
neoplastic effects are restricted to the upper respiratory tract with exposures
to concn below 5-10 ppm. Accordingly, the meta-analyses of the human data have
focused on the findings for respiratory cancer deaths in occupationally exposed
humans.
... describe the case of a 58-yr old man who swallowed 4 ounces of formalin (517 mg formaldehyde/kg) in a suicide attempt. The man
was found unconscious by a co-worker about 1 hr after his shift began. In the
emergency room, the subject regained consciousness but was lethargic. Lab
results indicated significant acidosis. Approx 3 hr after ingesting the formalin, the patient complained of abdominal
pain & began retching without emesis; he was admitted for observation &
treated with ethanol. The patient's abdominal pains became more severe & he
had difficulty breathing. At 5.5 hr after ingestion, the patient became obtund,
& both his respiratory rate & blood pressure fell significantly; he was
intubated & placed on 100% oxygen. Shortly thereafter, the patient began to
experience seizures; treatment with diazepam & phenytoin was unproductive,
but pancuronium was effective in treating the seizures. IV bicarbonate &
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, & leathery;
the esophagus & intestines appeared to be normal.
A 55-yr old woman and a 34-yr old man ingested, with suicidal intent, an
unknown amt of what was reported to have been formalin ... . The female patient was found in
a coma and admitted to the hospital with shock (systolic blood pressure 50 mm
Hg), respiratory insufficiency, and metabolic acidosis. The male patient, who
had a history of alcohol abuse, was also hospitalized with shock (systolic blood
pressure 60 mm Hg), respiratory insufficiency, and metabolic acidosis. Both
patients underwent hemodialysis and hemofiltration treatment. Analysis of the
formaldehyde samples ingested by both
patients showed no evidence that these products contained methanol, although it
was expected to have been detected. A chemical-toxicological screening /of blood
samples/ indicated that no drugs other than formaldehyde had been ingested ... . Three wk
after ingestion of formaldehyde, the
female patient died of cardiac failure refractory to catecholamine therapy. The
male patient developed adult respiratory distress syndrome and died 8 wk after
formaldehyde ingestion with signs of
cardiac failure.
Human lymphoblast mutants at the X-linked hprt locus have been examined by
Southern blot, Northern blot & DNA sequence analysis. A previous study had
shown that approx a third of the spontaneously arising mutants & half those
induced by formaldehyde showed no
alteration in restriction fragment pattern & thus were classified as point
mutation. In this report, these point mutants fall into 4 catagories: normal
size & amount of RNA, normal size but reduced amounts, reduced size RNA or
no RNA. Sequence analyses of cDNAs prepared from hprt mRNAs were performed on 1
spontaneous & 7 formaldehyde induced
mutants were base substitutions, all of which occurred at AT base-pairs. There
was an apparent hot spot, in that 4/6 independent mutants were AT----CG
transversions at one specific site. The remaining mutant had lost exon 8.
Human Toxicity Values:
The probable mean lethal adult dose is 1-2 oz.
Skin, Eye and Respiratory Irritations:
Contact with the skin causes irritation, tanning effect, and allergic
sensitization. Contact with eyes causes irritation, itching, & lacrimation.
...
Formaldehyde vapor is very irritating
to the mucous membranes and toxic to animals, including man.
Medical Surveillance:
Consider the skin, eyes, & resp tract in any placement or periodic
examination, esp if the patient has a history of allergies.
PRECAUTIONS FOR "CARCINOGENS": Whenever medical surveillance is indicated, in
particular when exposure to a carcinogen has occurred, ad hoc decisions should
be taken concerning ... /cytogenetic and/or other/ tests that might become
useful or mandatory. /Chemical Carcinogens/
... No biologic monitoring techniques exist at present, either for the
reliable determineation of formaldehyde
levels in tissue or for the determination of formaldehyde adducts formed with
macromolecules. Techniques are under development for nonspecific monitoring of
exposure through periodic assessment of chromosome damage (micronucleus
formation or sister chromatid exchange frequency) in workers exposed to formaldehyde.
Preemployment baseline data should be recorded for the respiratory tract,
liver, and skin condition of any worker who will be exposed to formaldehyde. Thereafter, periodic monitoring
should be conducted to detect symptoms of pulmonary or skin sensitization or
effects on the liver.
The assessment of formaldehyde
exposure can be accomplished through measurement of the metabolite formic acid.
Formic acid is also an endogenously produced substance formed by the degradation
of glycine. There was no information in the literature that showed a correlation
between urinary formic acid levels & formaldehyde exposure levels. This measurement
is also a poor indicator of the extent of formaldehyde absorption, due to the high
endogenous levels of formic acid. Urine Reference Ranges: Normal- normal
population level: 21 mg/l (endogenously produced formic acid); Exposed- not
established; Toxic- not established.
Respiratory Symptom Questionnaires: Questionnaires published by the American
Thoracic Society (ATS) & the British Medical Research Council have proven
useful for identifying people with chronic bronchitis. Certain pulmonary
function tests such as the FEV1 have been found to be better predictors of
chronic airflow obstruction.
Chest Radiography: Chest radiographs are widely used to assess pulmonary
disease. They are useful for detecting early lung cancer in asymptomatic people,
& especially for detecting peripheral tumors such as adenocarcinomas.
However, even though OSHA mandates this test for exposure to some toxicants such
asbestos, experts' views on the risk-to-benefit ratio in detection of pulmonary
disease conflict, so routine annual chest x-rays are not recommended for all
people.
Pulmonary Function Tests: The tests that have been found to be practical for
population monitoring include: Spirometry & expiratory flow-volume curves;
Determination of lung volumes; Diffusing capacity for carbon monoxide;
Single-breath nitrogen washout; Inhalation challenge tests; Serial measurements
of peak expiratory flow; Exercise testing.
Urine Albumin: Albuminuria has been shown to be a specific marker of
glomerular dysfunction. Tubular damage, however, can also result in increased
levels of albumin in the urine.
Urinary Beta-2-Microglobulin &/or Retinal Binding Protein: Measurements
for the presence of either of these low molecular weight proteins are useful in
detection of early impairment of proximal tubular function. However,
beta-2-microglobulin is unstable at urinary pH <6, & may degrade in the
bladder prior to collection & subsequent neutralization of the urine sample.
Measurement of retinal binding protein appears to be a better marker for early
tubular dysfunction due to its stability in the urine subsequent to collection
& analysis. However, retinal binding protein is produced in the liver &
not a constitutive protein of the kidney, so that its presence in the kidney
provides only indirect evidence of tubular damage.
Urinary Enzyme N-Acetylglucosaminidase: This lysosomal enzyme has shown
promise in assessment of subclinical nephrotoxic injury. This enzyme is not
normally filtered at the glomerulus due to its high molecular weight. In the
absence of glomerular injury, this enzyme will be detected in the urine as a
result of leakage or exocytosis from damaged, stimulated, or exfoliated renal
cells. The sensitivity of measurement for this enzyme has not been thoroughly
studied, but it's usefulness has shown some promise. However, this enzyme is
unstable at urinary pH >8, which could diminish the sensitivity of the
measurement due to enzyme degradation.
DNA-Protein Crosslinks: Measurement of DNA-protein crosslinks in white blood
cells may be a useful test for assessing formaldehyde exposure. In addition,
measurement of these crosslinks in other formaldehyde sensitive tissues, such as the
upper respiratory tract, may be a useful indicator of formaldehyde exposure. However, other
toxicants may cause similar crosslinks, so that the specificity of this test for
assessing only formaldehyde exposure is
questionable.
Routine Urinalysis: Performing a routine urinalysis including parameters such
as specific gravity, glucose, & microscopic exam may be useful for assessing
renal toxicity.
Urinary Alpha & Pi Isoenzymes of Glutathione S-Transferase:
Radio-immunological & Elisa techniques have been developed for quantitation
of /alpha/ & /pi/ isoenzymes of glutathione S-transferase, which are
constitutive proteins in the kidney. The /alpha/ isoenzyme is located only in
the proximal tubule, while the /pi/ isoenzyme is located in the distal
convoluted tubule, the loop of Henle, & the collecting ducts of the kidney.
Damage to epithelial cell membranes can result in the increased excretion of
these isoenzymes in the urine. This test for assessing renal tubular damage
appears to have many advantages over other available tests, such as: (1) the
/alpha/ & /pi/ isoenzymes are constitutive proteins in the kidney; (2) these
isoenzymes are stable in the urine; (3) the test is simple & reproducible;
& (4) due to selective localization of the isoenzymes, differential
diagnosis of specific tubular damage is possible. In addition, increased levels
of these isoenzymes were seen in patients previously exposed to nephrotoxicants
where conventional tests for kidney function were normal, indicating a high
degree of sensitivity.
Populations at Special Risk:
Mean formaldehyde levels are highest
in hospital autopsy rooms compared with other commercial settings. /Hospital
autopsy workers are possibly exposed/.
Release of /formaldehyde/ vapors in
mobile homes has been associated with headache & pulmonary & dermal
irritation. /Occupants of mobile homes are possibly exposed/.
Two populations of humans have received considerable attention in the
literature as being particularly sensitive to formaldehyde exposure following inhalation
and/or dermal routes. The first population is asthmatics, and concern focuses on
the changes in lung function parameters that formaldehyde may produce ... . Most of these
studies concluded that there is no evidence of incr airway reactivity as a
result of formaldehyde exposure in
either normal or asthmatic individuals. ... The second population of potential
concern is people with dermal sensitization ... Formaldehyde liquid, but neither the gaseous
phase nor formalin, is considered to be
a dermal sensitizer ... . Anaphylactic reactions have been reported ... . Dermal
allergic reactions have also been reported in doctors and nurses exposed to
formaldehyde ... as well as in
fiberglass workers ... .
Workers in industries where formaldehyde is used or released may receive
potentially high exposures. Members of the general population who live in newly
constructed homes or homes where pressed wood products have recently been
installed may be exposed to high levels of formaldehyde by inhalation for short periods
of time until the latent formaldehyde
has been released. Exposure in mobile homes are expected to be higher than
conventional homes due to their lower rate of air exchange ... . Members of the
general population that handle large amt of permanent press fabrics treated with
formaldehyde-releasing resins may also
receive potentially high exposures. The use of some cosmetics, such as nail
hardeners, may result in high short-term exposure.
Smokers and persons who live in a home with a cigarette smoker also may be
exposed to higher levels of formaldehyde. Environmental tobacco smoke,
which is a combination of diluted sidestream smoke released form a cigarette's
burning end and mainstream smoke exhaled by an active smoker, can contribute
10-25% (0.1-1 mg/day) of the total average indoor exposure to formadehyde ... .
Probable Routes of Human Exposure:
... /VAPORS/ GIVEN OFF DURING HOT MOLDING OF SYNTH RESINS (/IS A/ COMMON
SOURCE OF EXPOSURE) ... A SURVEY OF 6 FUNERAL HOMES ... REVEALED MEAN CONCN, IN
DIFFERENT ESTABLISHMENTS, BETWEEN 0.25 & 1.39 PPM. ... /EXPOSURES ARE
ENCOUNTERED/ IN PHENOL-FORMALDEHYDE
RESIN MOULDING PLANT ... /FROM WHICH/ CHRONIC AIRWAY OBSTRUCTION LOWERED FORCED
EXPIRATORY VOL/FORCED VOL CAPACITY RATIO & EYE, NOSE & THROAT IRRITATION
& LOWER RESP TRACT SYMPTOMS /HAVE BEEN OBSERVED/.
... /EXPOSURES TO/ FORMALDEHYDE VAPOR
EMISSIONS IN PERMANENT-PRESS FABRICS INDUSTRY (8 PLANTS) /HAVE BEEN REPORTED IN
WHICH/ CONCN RANGING ... FROM 0.3 TO 2.7 PPM (IN SEWING AREA) WITH AVG OF 0.68
PPM /WERE DETECTED/. COMPLAINTS CONSISTED OF ANNOYING ODOR (ODOR THRESHOLD,
BELOW 1.0 PPM), CONSTANT PRICKLING IRRITATION OF MUCOUS MEMBRANES &
DISTURBED SLEEP.
NIOSH (NOES Survey 1981-1983) has statistically estimated that 1,329,322
workers (441,902 of these are female) are potentially exposed to formaldehyde in the US(1). The NOES Survey
does not include farm workers(SRC). Occupational exposure to formaldehyde may occur through inhalation and
dermal contact with this compound at workplaces where formaldehyde is produced or used(2).
Monitoring data indicate that the general population may be exposed to formaldehyde via inhalation of ambient air,
ingestion of food, and dermal contact with cosmetic and aerosol products
containing formaldehyde(2).
Humans are exposed to formaldehyde
from a variety of sources. The major source of atmospheric discharge is from
combustion processes specifically from auto emissions and also from the
photooxidation of hydrocarbons in auto emissions(1,2). Additional exposure to
formaldehyde emissions comes from its
use as an embalming fluid in anatomy labs, morgues, etc and its use as a
fumigant and sterilant(1). Resin treated fabric, rugs, paper, etc and materials
such as particle board and plywood which use resin adhesives and foam insulation
release formaldehyde which may build up
in homes and occupational atmospheres(1,2). Contact with industrial waste water,
especially from lumber related operations where formaldehyde is used in adhesives, has
resulted in the Pacific Northwest, Northeast, parts of Texas, and lumber areas
of the south(1)(SRC). The estimated daily intake of formaldehyde among exposed Finnish workers is
3000 ug, whereas heavily exposed workers (particle-board and glue production,
foundry work) is 10,000 ug(3).
In a 12-week study of exposure in a gross anatomy lab of a medical school,
44% of breathing room samples and 11% of ambient air samples were >1.0 ppm
the ceiling recommended by ACGIH; Half the breathing zone samples were between
0.6-1.0 ppm and the range was 0.3-2.63 ppm(1). A 1976 report estimates that 8000
US workers were potentially exposed to formaldehyde during its production(3). A more
recent estimate of the number of exposed workers in industries producing and
using formaldehyde and its derivatives
range from 1.4-1.75 million(2). Concentrations of formaldehyde in occupational areas dating from
the 1960's and early 1970's are: textile plant 0-2.7 ppm, 0.68 ppm avg; garment
factory 0.9-2.7 ppm; clothing store 0.9-3.3 ppm; laminating plant 0.04-10 ppm;
funeral homes 0.09-5.26 ppm, 0.25-1.39 ppm avg; resin manufacture and paper
production 16-30 ppm; paper conditioning 0.9-1.6 ppm; wood processing 31.2 ppm
max(2). Concns in occupational settings dating from the late 70's are: textile
plants 0.1-0.5 ppm, 0.2 ppm avg; shoe factory 0.9-2.7 ppm, 1.9 ppm avg; particle
board plant 0.1-4.9 ppm, 1.15 ppm avg; plywood plant 0.1-1.2 ppm, 0.35 ppm avg;
wooden furniture manufacturing plant 0.1-5.4 ppm, 1.35 ppm avg; adhesive plants
0.8-3.5 ppm, 1.75 ppm avg; foundries 0.05-2.0 ppm, 0.6 ppm avg; construction
sites 0.5-7.0 ppm, 2.8 ppm avg; hospitals and clinics 0.05-3.5 ppm, 0.7 ppm
avg(2). More recent survey results for occupational environments include:
fertilizer production 0.2-1.9 ppm; dyestuffs <0.1-5.8 ppm; textile
manufacture <0.1-1.4 ppm; resins (foundry) <0.1-5.5 ppm; bronze foundry
0.12-0.8 ppm; iron foundry <0.02-18.3 ppm; treated paper 0.14-0.99 ppm;
hospital autopsy room 2.2-7.9 ppm; plywood industry 1.0-2.5 ppm; urea-formaldehyde foam applicators <0.08-2.4
ppm(4).
Potential occupational exposure to formaldehyde are as follows: agricultural
workers, anatomists, beauticians, biologists, bookbinders, botanists, chemical
production workers, cosmetic formulators, crease-resistant textile finishers,
disinfectant makers, disinfectors, dress-goods shop personnel, electrical
insulation makers, embalmers, embalming fluid makers, fireproofers, formaldehyde production workers, formaldehyde resin makers, foundry employees,
fumigators, fur processors, furniture makers, glue and adhesive makers, hide
preservers, histology technicians (including necropsy and autopsy technicians),
ink makers, lacquerers and lacquer makers, medical personnel (including
pathologists), mirror manufacturers, paper makers, particle-board makers,
photographic film makers, plastic workers, plywood makers, rubber makers,
taxidermists, textiles mordanters and printers, textiles waterproofers, varnish
workers, wood preservers(1).
The avg concn of formaldehyde in
workroom air in formaldehyde and resin
manufacturing plants ranged from 0.1-14.2 mg/cu m(1). The avg concn of formaldehyde in workroom air of plywood mills,
particle-board mills, furniture factories, other wood product and paper mills
ranged from 0.08-7.4 mg/cu m(1). The avg concn of formaldehyde in workroom air in textile mills
and garment factories ranged from 0.1 to 1.9 mg/cu m(1). The avg concn of formaldehyde in workroom air in foundries and
other industrial facilities ranged from 0.04 to 38.2 mg/cu m(1). The avg concn
of formaldehyde in workroom air in
mortuaries, hospitals, and laboratories ranged from 0.05 to 4.2 mg/cu m(1). The
avg concn of formaldehyde in workroom
air in building sites, agriculture, forestry, and misc other activities ranged
from <0.1 to 4.3 mg/cu m(1).
Cigarette smoke and products of combustion contain formaldehyde(1). Cigarette smoke contains 15
to 20 mg formaldehyde per cigarette(1).
Avg formaldehyde exposure from passive
smoking is between 0.23 to 0.27 ppm(1). A 'pack-a-day' smoker may inhale as much
as 0.4-2.0 mg formaldehyde(1).
Several studies have been conducted to determine exposure of students in
laboratories(1). The concn of formaldehyde in the breathing zone at
dissecting tables and in the ambient air in a medical school in the United
States was found to be >1.2 mg/cu m in 44% of the breathing zone samples and
11 ambient air samples; 50% of the breathing zone samples contained 0.7-1.2
mg/cu m, with a range of 0.4-3.2 mg/cu m(1). During the 1982-82 academic year,
the airborne concn of formaldehyde at a
university in the US was 7-16.5 ppm in the laboratory, 1.97-2.62 ppm in the
stockroom, and <1 ppm in the public hallway(1). In another study, of 253
samples of air taken during laboratory dissection classes at a university in the
US, 97 contained concns above the detection limit of 0.01 mg/cu m; all but four
samples had levels <1.2 mg/cu m(1). The avg concn detected was 0.5 mg/cu
m(1).
Average Daily Intake:
AIR INTAKE: Assume 1 to 100 ug/cu m(1), 20 ug to 2,000 ug formaldehyde(SRC).
In Sweden between Dec 1986 to Aug 1987, the mean yearly exposure to formaldehyde from air pollution was 1.2 ug/cu
m(1). The estimated daily exposure of the Finnish population to formaldehyde from community air is 100 ug and
from the home environment, 1,000 ug(2).
Minimum Fatal Dose Level:
Approximate Minimum Lethal Dose (MLD) (150-lb man): 30 ml
Male single oral ingestion 517 mg/kg
Emergency Medical Treatment:
Emergency Medical Treatment:
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The following Overview, *** FORMALDEHYDE ***, is relevant for this HSDB record chemical. |
| Life Support: |
o This overview assumes that basic life support measures
have been instituted. |
| Clinical Effects: |
SUMMARY OF EXPOSURE
0.2.1.1 ACUTE EXPOSURE
o Formaldehyde may be irritating to the eyes, skin, and
mucous membranes. Ingestion may cause corrosive injury
to the gastrointestinal mucosa, with nausea, vomiting,
pain, hematemesis, and perforation. Systemic effects
include CNS depression, seizures, coma, jaundice,
albuminuria, hematuria, anuria, and metabolic acidosis.
Acute health effects include burning in the eyes, nose,
throat; skin rashes, nausea, coughing and chest
tightness. Sensitive individuals may have reactions at
concentrations as low as 0.1 ppm.
o Respiratory tract irritation, rhinitis, anosmia, cough,
dyspnea, wheezing, tracheitis, bronchitis,
laryngospasm, pulmonary edema, headache, weakness,
dizziness, and palpitations may result from inhalation.
o Dermatitis, brownish discoloration of the skin,
urticaria, and pustulovesicular eruptions, may develop
from dermal exposure. Concentrated solutions can
cause coagulation necrosis.
o Irritation, lacrimation, and conjunctivitis may develop
with exposure to vapors. Eye exposure to solutions
with high formaldehyde concentrations may produce
severe corneal opacification and loss of vision.
Solutions containing low formaldehyde concentrations
may produce transient discomfort and irritation.
o This management includes information pertaining to the
toxicity of formaldehyde, a one carbon aldehyde, as
well as formalin, a mixture of formaldehyde in various
concentrations of methanol.
VITAL SIGNS
0.2.3.1 ACUTE EXPOSURE
o Shock may develop with severe exposures. Tachypnea may
develop in patients with metabolic acidosis. Reduction
in body temperature may be seen.
HEENT
0.2.4.1 ACUTE EXPOSURE
o IRRITATION of the eyes, nose, and throat may occur
following exposure to formaldehyde OR fumes from
urea-formaldehyde foam and adhesive resins.
o Corneal opacification and loss of vision may occur
following direct eye splash exposure to solutions
containing high concentrations of formaldehyde.
Transient discomfort and irritation may result from eye
exposure to solutions containing low concentrations of
formaldehyde.
CARDIOVASCULAR
0.2.5.1 ACUTE EXPOSURE
o Hypotension and cardiovascular collapse may occur with
severe ingestion.
RESPIRATORY
0.2.6.1 ACUTE EXPOSURE
o Inhalation of formaldehyde vapors at elevated
concentrations may result in upper respiratory tract
irritation and coughing. Severe exposure may result in
serious lower respiratory effects, such as bronchitis,
pulmonary edema, or pneumonia. Reactive airways may
develop in susceptible individuals.
o Respiratory distress and ARDS has been reported
following ingestion or transdermal absorption of
formaldehyde-containing compounds.
NEUROLOGIC
0.2.7.1 ACUTE EXPOSURE
o Lethargy and coma may occur following large ingestions
or marked inhalation exposure.
0.2.7.2 CHRONIC EXPOSURE
o Chronic exposure may result in malaise, headache,
sleeping disturbances and irritability.
GASTROINTESTINAL
0.2.8.1 ACUTE EXPOSURE
o Nausea, vomiting, and severe abdominal pain may occur
following ingestion. Corrosive gastritis, hematemesis,
and edema and ulceration of the esophagus may occur.
Strictures and perforation are possible delayed
complications.
HEPATIC
0.2.9.1 ACUTE EXPOSURE
o Hepatotoxicity has been associated with inhalational
exposure in animals and has been suggested to occur in
humans.
o Hyperbilirubinemia has been reported following
ingestion.
o Biliary sclerosis occurred following formalin injection
into a hydatid cyst.
GENITOURINARY
0.2.10.1 ACUTE EXPOSURE
o Nephritis and acute renal failure may occur.
Membranous nephropathy has been associated with
formaldehyde exposure.
ACID-BASE
0.2.11.1 ACUTE EXPOSURE
o Lactic acidosis may occur.
HEMATOLOGIC
0.2.13.1 ACUTE EXPOSURE
o Intravascular hemolysis has been reported in dialysis
patients receiving doses of formaldehyde during
treatment.
DERMATOLOGIC
0.2.14.1 ACUTE EXPOSURE
o Allergic dermatitis and rash may occur.
IMMUNOLOGIC
0.2.19.1 ACUTE EXPOSURE
o Antibodies to formaldehyde (Types I and II reactions)
have been measured in exposed persons with clinical
effects ranging from irritation to severe
hypersensitivity reactions. Type IV reactions may
result in allergic contact dermatitis. Immunologic
reactions may be delayed by hours to months.
o Asthma-like signs and symptoms have been reported.
Evidence of formaldehyde sensitization or allergy
causing true asthma is inconclusive. Respiratory
effects do not consistently correlate with the
development of formaldehyde-specific immunoglobulins.
o Membranous nephropathy has been associated with
immunologic reaction to suspected formaldehyde
exposure.
0.2.19.2 CHRONIC EXPOSURE
o Allergic contact dermatitis, eczema and other signs
have been attributed to formaldehyde sensitivity.
REPRODUCTIVE HAZARDS
o Formaldehyde has not been shown definitely to be
teratogenic in animals. Formaldehyde probably presents
little or no risk as a potential human teratogen.
o Menstrual disorders have been reported in women
occupationally exposed to formaldehyde, but these
results are controversial. In experimental animal
studies, some effects on spermatogenesis have been
reported.
o Occupational exposure at recommended limits is not
thought to present a reproductive risk. Formaldehyde
exposure among female hospital workers did not correlate
with an increase in spontaneous abortion in one study,
but did correlate in another.
1. Low-birthweight children have been reported in female
workers exposed to urea-formaldehyde resin, but studies
are inconclusive. Formaldehyde appears to cross the
placental barrier in mice.
CARCINOGENICITY
0.2.21.2 HUMAN OVERVIEW
o Formaldehyde is a probable human carcinogen (IARC 2A
Limited evidence in humans and sufficient evidence in
animals). In another rating system formaldehyde is
classified as B1: probable human carcinogen. Basis
for Classification: Based on limited evidence in
humans, and sufficient evidence in animals (HSDB,
2002).
1. Human data include nine studies that show
statistically significant associations between
site-specific respiratory neoplasms and exposure to
formaldehyde or formaldehyde-containing products
(HSDB, 2002). Occupational exposure to formaldehyde
has been linked to the development of buccal and
nasopharyngeal metaplasia/neoplasia, and to a lesser
extent cancers of the nasal cavities.
2. Formaldehyde's role in lower respiratory tract cancer
etiology has not been substantiated. Consensus on
data collection and analysis methods will be necessary
to evaluate the link between formaldehyde and lung
cancer.
3. ANIMAL STUDIES - An increased incidence of nasal
squamous cell carcinomas was observed in long-term
inhalation studies in rats and in mice. The
classification of B1 is further supported by in vitro
genotoxicity data and formaldehyde's structural
relationships to other carcinogenic aldehydes such as
acetaldehyde (HSDB, 2002).
GENOTOXICITY
o Formaldehyde appears to be mutagenic. The basis for its
genetic activity is its ability to form cross-links in
DNA and proteins. |
| Laboratory: |
o FORMALDEHYDE PLASMA LEVELS are not widely available, but
may help in dialysis monitoring.
o Monitor acid base status in symptomatic patients. Monitor
liver function tests. Monitor hematocrit and hemoglobin
concentration in dialysis patients repeatedly exposed
parenterally to formaldehyde. Monitor blood METHANOL
levels after significant formalin ingestion.
o Pulmonary function testing and nasal and bronchial
provocation tests may be recommended in patients with
signs and symptoms of reactive airways dysfunction
following inhalation of formaldehyde. |
| Treatment Overview: |
ORAL EXPOSURE
o EMESIS: Ipecac-induced emesis is not recommended
because of the potential for cardiovascular instability.
o DILUTION: Immediately dilute with 4 to 8 ounces (120 to
240 mL) of milk or water (not to exceed 4 ounces/120 mL
in a child).
o After ingestion of concentrated formaldehyde, gastric
lavage with a soft small-bore NG tube may facilitate
removal. Risk of further mucosal injury should be
weighed against potential benefit. Although no data on
adsorption to activated charcoal could be found, it
should be considered following lavage, although it may
obscure endoscopy findings.
o ACTIVATED CHARCOAL: Administer charcoal as a slurry
(240 mL water/30 g charcoal). Usual dose: 25 to 100 g
in adults/adolescents, 25 to 50 g in children (1 to 12
years), and 1 g/kg in infants less than 1 year old.
o MONITOR ECG AND VITAL SIGNS and acid base status.
Monitor methanol levels.
o ENDOSCOPY: Because acid ingestion may cause severe
gastric burns with relatively few initial signs and
symptoms, endoscopic evaluation is recommended within 24
hours in any patient with a definite history of
ingesting a strong acid, even if asymptomatic. If burns
are found, follow 10 to 20 days later with a barium
swallow.
o PHARMACOLOGIC TREATMENT: Corticosteroids are
controversial. Consider use in second degree burns
within 48 hours of ingestion in patients without
gastrointestinal bleeding or evidence of perforation.
Antibiotics are indicated for suspected perforation or
infection and in patients receiving corticosteroids.
o SURGICAL OPTIONS: Initially, if severe esophageal burns
are found a string may be placed in the stomach to
facilitate later dilation. Insertion of a specialized
nasogastric tube after confirmation of a circumferential
burn may prevent strictures. Dilation is indicated
after 2 to 4 weeks if strictures are confirmed; if
unsuccessful, either colonic intraposition or gastric
tube placement may be performed. Consider early
laparotomy in patients with severe esophageal and/or
gastric burns.
o Administer ethanol or fomepizole in patients with
significant methanol levels. HEMODIALYSIS should be
considered in those patients with severe acid-base
disturbances refractory to conventional therapy, or in
cases with significant methanol levels.
o HYPOTENSION: Infuse 10 to 20 mL/kg isotonic fluid,
place in Trendelenburg position. If hypotension
persists, administer dopamine (5 to 20 mcg/kg/min) or
norepinephrine (0.1 to 0.2 mcg/kg/min), titrate to
desired response.
INHALATION EXPOSURE
o INHALATION: Move patient to fresh air. Monitor for
respiratory distress. If cough or difficulty breathing
develops, evaluate for respiratory tract irritation,
bronchitis, or pneumonitis. Administer oxygen and
assist ventilation as required. Treat bronchospasm with
beta2 agonist and corticosteroid aerosols.
EYE EXPOSURE
o PREHOSPITAL CARE: Irrigation with sterile water or
saline, a commercial eye irrigation kit, or tap water
should be started prior to admission.
o MEDICAL FACILITY: Irrigate with sterile 0.9% saline for
at least an hour or until the cul-de-sacs are free of
particulate matter and returned to neutrality (confirm
with pH paper).
DERMAL EXPOSURE
o DECONTAMINATION: Remove contaminated clothing and wash
exposed area thoroughly with soap and water. A
physician may need to examine the area if irritation or
pain persists. |
| Range of Toxicity: |
o INGESTION of as little as 30 mL of a 37% solution of
formaldehyde has resulted in death in an adult. |
Antidote and Emergency Treatment:
Decontamination: Dilute with milk or water in alert patients as a first aid
measure may reduce corrosive effects at the scene. If ingestion has occurred
within 1 hr before presentation, gentle gastric aspiration with a soft
nasogastric tube may limit systemic absorption. There is little evidence to
support the use of activated charcoal to absorb formate or formaldehyde. ... Elimination enhancement:
Severe acidosis & deteriorating vital signs are indications for considering
dialysis, but the literature does not contain adequate case studies to guide
treatment. Aggressive sodium bicarbonate therapy & frequent monitoring of
arterial blood gases may be useful. There are no antidotes. Supportive care: 1.
Monitor electrolytes, fluids, acid-base, & kidney function closely. 2. Watch
for signs of GI hemorrhage & perforation with serial vital signs, abdominal
exams, & complete blood counts. 3. Check blood methanol levels & treat
accordingly in formalin ingestions. 4.
Fibrosis of stomach has required partial gastrectomy in the past.
Irrigate eyes with water. Wash contaminated areas of body with soap and
water. Gastric lavage (stomach wash), if swallowed, using 1% ammonium carbonate
and followed by saline catharsis. Oxygen, if indicated.
Basic Treatment: Skin- Treated as any burn to prevent allergic contact
dermatitis, exposure to formaldehyde or
formaldehyde-containing products should
be minimized. Inhalation- Patients should be removed from exposure. If symptoms
persist, hospitalization may be required. Very high levels (100 ppm) may be
lethal. Pulmonary damage may occur. Oral- high concn of formaldehyde may be irritating to the GI
tract. Ingestion can result in metabolic responses similar to methanol
poisoning. Hemodialysis is efficacious just as in methanol poisoning &
should be considered if metabolic acidosis occurs.
Basic treatment: Establish a patent airway. Suction if necessary. Watch for
signs of respiratory insufficiency and assist ventilations if necessary.
Aggressive airway management may be necessary. Administer oxygen by
nonrebreather mask at 10 to 15 L/min. Anticipate seizures and treat if necessary
... . Monitor for shock and treat if necessary ... . Monitor for pulmonary edema
and treat if necessary ... . For eye contamination, flush eyes immediately with
water. Irrigate each eye continuously with normal saline during transport ... .
Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200
ml of water for dilution if the patient can swallow, has a strong gag reflex,
and does not drool. Administer activated charcoal ... . /Aldehydes and related
compounds/
Advanced treatment: Consider orotracheal or nasotracheal intubation for
airway control in the patient who is unconscious or in respiratory arrest.
Intubation should be considered at the first sign of upper airway obstruction
caused by edema. Positive pressure ventilation techniques with a bag-valve-mask
device may be beneficial. Start an IV with D5W /SRP: "To keep open", minimal
flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for
signs of fluid overload. Treat seizures with diazepam ... . For hypotension with
signs of hypovolemia, administer fluid cautiously. Consider vasopressors if
patient is hypotensive with a normal fluid volume. Watch for signs of fluid
overload ... . Consider drug therapy for pulmonary edema ... . Use proparacaine
hydrochloride to assist eye irrigation ... . /Aldehydes and related compounds/
Animal Toxicity Studies:
Evidence for Carcinogenicity:
CLASSIFICATION: B1; probable human carcinogen. BASIS FOR CLASSIFICATION:
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.
HUMAN CARCINOGENICITY DATA: Limited. ANIMAL CARCINOGENICITY DATA: Sufficient.
A2. A2= Suspected human carcinogen.
Evaluation: There is limited evidence in humans for the carcinogenicity of
formaldehyde. There is sufficient
evidence in experimental animals for the carcinogenicity of formaldehyde. Overall evaluation: Formaldehyde is probably carcinogenic to
humans (Group 2A).
Non-Human Toxicity Excerpts:
INHALATION ... BY ANIMALS CAUSES PROMPT & SEVERE IRRITATION OF EYES &
RESP TRACT. ... EDEMA & HEMORRHAGES OF ... LUNG, & SIGNS OF HYPEREMIA
& PERIVASCULAR EDEMA IN THE LIVER AND KIDNEYS.
PROLONGED EXPOSURE OF RABBITS TO FORMALDEHYDE CAUSED ACID PHOSPHATASE,
TWEEN-60-ESTERASE, NAPHTHOL-AS-D-ACETATE-ESTERASE, PROLINE-OXIDASE &
HYDROXYPROLINE-2-EPIMERASE ACTIVITIES TO INCREASE & LEUCYL-AMINOPEPTIDASE
& BETA-GLUCURONIDASE TO DECREASE. IT INDUCED BRONCHIAL CELL HYPERPLASIA WITH
HYPERMUCIGENESIS, EXTRUSION OF BRONCHIAL CELLS, BRONCHIOLAR HYPERMUCIGENESIS,
PARCELLARY SQUAMOUS METAPLASIA OR NECROBIOSIS OF EPITHELIA.
CD-1 MICE WERE GIVEN UP TO 185 MG/KG BODY WT FORMALDEHYDE BY GAVAGE ON DAYS 6-15 OF
GESTATION. HIGHEST DOSE WAS ... TOXIC TO DAMS, BUT NO EMBRYOTOXICITY OR
TERATOGENICITY WAS SEEN WITH ANY DOSE.
ACUTE ... EFFECTS ... IN RATS ... /& OTHER EXPTL ANIMALS/ TO LOW (LESS
THAN 1 PPM) OR MODERATE (10-50 PPM) ... /OF/ VAPOR RESULTED IN INCREASED AIRWAY
RESISTANCE, DECR SENSITIVITY OF NASOPALATINE NERVE, IRRITATION OF EYES & OF
RESP SYSTEM, & CHANGES IN HYPOTHALAMUS. EXPOSURE TO HIGH DOSES (ABOVE 100
PPM) ... CAUSED SALIVATION, ACUTE DYSPNEA, VOMITING, CRAMPS & DEATH ... .
EXPOSURE BY INHALATION FOR UP TO 90 DAYS PRODUCED INTERSTITIAL INFLAMMATION
IN LUNGS OF DOGS, RATS, MONKEYS, RABBITS & GUINEA-PIGS. ... HAIR
DEPIGMENTATION WAS OBSERVED IN BLACK MICE AT SITE OF SC INJECTION OF 100 UG
FORMALDEHYDE. ... MICE TREATED WITH
FORMALDEHYDE ON SKIN DEVELOPED SEVERE
LIVER DAMAGE.
GROUPS OF 119-120 MALE & 120 FEMALE FISCHER 344 RATS, 7 WK OF AGE WERE
EXPOSED TO 0, 2, 5.6 OR 14.3 PPM (0, 2.5, 6.9, 17.6 MG/CU M) ... GREATER THAN
97.5% PURE VAPOR BY WHOLE-BODY EXPOSURE FOR 6 HR/DAY ON 5 DAYS/WK FOR UP TO 24
MO, FOLLOWED BY 6 MO OBSERVATION PERIOD. ... LIFE-TABLE ANALYSIS OF ... DATA
REVEALED SIGNIFICANT INCR (P< 0.0167) IN INCIDENCES OF SQUAMOUS-CELL
CARCINOMAS IN /NASAL CAVITY OF RATS/ EXPOSED TO 14.3 PPM FORMALDEHYDE VAPOR; NO OTHER NEOPLASM WAS
INCREASED SIGNIFICANTLY. THE INCIDENCE OF A VARIETY OF NON-NEOPLASTIC LESIONS
WERE SIGNIFICANTLY INCREASED IN RATS EXPOSED TO FORMALDEHYDE.
GROUPS OF 6 MALE CYNOMOLGUS MONKEYS ... & 10 MALE & 10 FEMALE SYRIAN
GOLDEN HAMSTERS WERE EXPOSED TO 0, 0.2, 1.0 OR 3 PPM (0, 0.24, 1.2 OR 3.7 MG/CU
M) FORMALDEHYDE VAPOR (98.8% PURE) FOR
22 HR/DAY ON 7 DAYS/WK FOR 26 WK. SQUAMOUS METAPLASIA OF NASAL TURBINATES WERE
EVIDENT IN 6/6 MONKEYS EXPOSED TO 3 PPM & IN 1/6 EXPOSED TO 1 PPM. ... NO
EXPOSURE-RELATED EFFECTS WERE DEMONSTRATED IN HAMSTERS.
REPEATED INHALATION EXPOSURE TO VAPORS AT 15 PPM IN MALE CHARLES RIVER CD
RATS & MALE C57BL6/F1 MICE WAS STUDIED. RATS WERE RELATIVELY INSENSITIVE TO
IRRITANT ACTION WHILE MICE WERE MORE SENSITIVE, SHOWING COMPARABLE REDUCTION IN
TIDAL VOL, BUT GREATER DECR IN RESPIRATORY RATE & MINUTE VOL. CARBON DIOXIDE
PRODUCTION AS WELL AS BODY TEMP WERE DECR TO GREATER EXTENT IN MICE THAN IN
RATS.
With Salmonella typhimurium, the minimum concn required to induce
8-azaguanine resistance was 170 uM.
15 ppm formaldehyde caused an initial
wave of cell replication in the nasal cavity of mice and rats 18 hr after a 6 hr
exposure. The /percentage/ of replicating cells remained ... elevated for 3-5
days and then began to decrease. Similar elevations occurred following 3 daily
exposures to 6 ppm formaldehyde in rats,
but not mice. ...
... Threshold concn of sensitization effect of /formaldehyde/ in guinea pigs was 0.5 mg/cu m.
... Quantitative changes were seen only in B-lymphocytes, whereas T-lymphocytes
were essentially unchanged. At 3 mg/cu m the sensitization effect was seen in
all the animals. The T-lymphocytes decreased substantially but B-lymphocytes
increased. ...
... Primary hamster embryo cells were treated by exposure to gaseous formaldehyde or by incorporation into the
medium, a dose-related incr in the frequency of SA7 virus transformation was
produced. ... Length of chemical treatment and the time interval before
subsequent addition of transforming virus was critical, with 2 hr treatment
times being most efficient. ... 2.2 ug/ml produced significantly enhanced viral
transformation. ...
... RATS /EXPOSED/ CONTINUOUSLY DURING PREGNANCY TO ... VAPORS (1 MG/CU M)
... /SHOWED/ NO VISIBLE FETAL MALFORMATIONS. ASCORBIC ACID CONTENT OF TREATED
FETUSES WAS LOWER THAN CONTROLS BUT BODY WT WAS INCR. FETAL DNA CONTENT WAS DECR
& RNA CONTENT WAS INCR.
GROUPS OF 100 MALE SPRAGUE-DAWLEY RATS WERE EXPOSED FROM 9 WK OF AGE TO (A)
14.3 PPM (17.44 MG/CU M) FORMALDEHYDE
(PURITY UNSPECIFIED) & 10 PPM (16.2 MG/CU M) HYDROGEN CHLORIDE GAS BEFORE
DILN IN EXPOSURE CHAMBER TO MAXIMIZE FORMATION OF BIS(CHLOROMETHYL)ETHER; (B)
14.1 PPM (17.2 MG/CU M) FORMALDEHYDE
& 9.5 PPM 115.48 MG/CU M) HYDROGEN CHLORIDE NOT MIXED BEFORE INTRODUCTION
INTO ... CHAMBER; (C)14.2 PPM (17.32 MG/CU M) FORMALDEHYDE VAPOR ALONE; (D) HYDROGEN
CHLORIDE GAS ALONE (10.2 PPM); OR (E) AIR (SHAM-EXPOSED CONTROLS). AFTER ... 382
EXPOSURES OVER ... 588 DAYS (19.4 MO), 10 HISTOLOGICALLY CONFIRMED, GROSSLY
VISIBLE NASAL SQUAMOUS-CELL CARCINOMAS WERE OBSERVED IN RATS EXPOSED TO FORMALDEHYDE ALONE; NONE WERE SEEN IN CONTROLS
OR IN RATS EXPOSED TO HYDROGEN CHLORIDE ALONE ... COMBINED EXPOSURE TO FORMALDEHYDE & HYDROGEN CHLORIDE DID NOT
PRODUCE STATISTICALLY SIGNIFICANT INCR IN INCIDENCE OF NASAL SQUAMOUS-CELL
CARCINOMAS OVER THAT OBTAINED WITH FORMALDEHYDE ALONE. ...
EXPOSURE OF CULTURED MONKEY KIDNEY CELLS TO 1-16 MMOL ... FOR 15 MIN RESULTED
IN FORMATION OF SHORT RNA CHAINS; CONCN EQUAL TO OR GREATER THAN 2 MMOL PRODUCED
COMPLETE INHIBITION OF THYMIDINE INCORPORATION & CELL GROWTH. ALMOST
COMPLETE REVERSAL OF THESE EFFECTS WERE SEEN WITHIN 24 HR AFTER REMOVAL OF FORMALDEHYDE; SUCH RECOVERY WAS NOT
ACCOMPANIED BY UNSCHEDULED DNA SYNTHESIS.
Addition of aroclor-induced post-mitochondrial supernatant reduced the
mutagenicity of formaldehyde in the
bacterial cells.
DNA-protein crosslinks have been formed in the nasal respiratory mucosa of
Fischer-344 rats exposed for 3 hr to selected concentrations of (3)H- and
(14)C-formaldehyde. ... In rats depleted
of glutathione and exposed to 10 ppm of (3)H-formaldehyde and (14)C-formaldehyde, the (3)H/(14)C ratio of the
fraction of the DNA that was crosslinked to proteins was significantly (39 + or
- 6%) higher than that of the inhaled gas. This suggests an isotope effect,
either on the formation of DNA-protein crosslinks by labeled formaldehyde or on the oxidation of labeled
formaldehyde catalyzed by formaldehyde or aldehyde dehydrogenase. These
results suggest that the residual (unoxidized) formaldehyde present in the nasal mucosa of
rats exposed to (3)H- and (14)C-formaldehyde may be "enriched" in 3-formaldehyde relative to (14)C-formaldehyde which can bind to DNA resulting
in an isotope ratio higher than that of the inhaled gas. The isotope effect on
the oxidation of (3)formaldehyde and
(14)C-formaldehyde suggests that
previous estimates of the amount of formaldehyde covalently bound to nasal mucosal
DNA may have been too large.
Glutathione is required for the oxidation of formaldehyde to formate catalyzed by formaldehyde dehydrogenae. The effects of glutathione depletion on the mechanisms of labeling of macromolecules in the rat nasal mucosa and bone marrow by (3)H-formaldehyde and (14)C-formaldehyde were investigated. Male rats were exposed for 3 hr to atmosphere containing (3)H-formaldehyde and (14)C-formaldehyde at concentrations of 0.9, 2,4,6, or 10 ppm, 1 day after a single 3 hr preexposure to the same concentration of unlabeled formaldehyde. Two hours prior to the second exposure, the animals were injected either with phorone (300 mg/kg, ip) or with corn oil. The concentration of nonprotein sulfhydryls in the nasal respiratory mucosa of phorone-injected rats was decreased to 10% of that of corn oil-injected rats. The metabolic incorporation of (3)H-formaldehyde and (14)C-formaldehyde into DNA, RNA and proteins in the respi