INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY
ENVIRONMENTAL HEALTH CRITERIA 89
FORMALDEHYDE
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Geneva, 1989
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WHO Library Cataloguing in Publication Data
Formaldehyde.
(Environmental health criteria ; 89)
1.Formaldehyde
I.Series
ISBN 92 4 154289 6 (NLM Classification: QV 225)
ISSN 0250-863X
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CONTENTS
ENVIRONMENTAL HEALTH CRITERIA FOR FORMALDEHYDE
1. SUMMARY AND CONCLUSIONS
1.1. Physical and chemical properties, and analytical methods
1.2. Sources of human and environmental exposure
1.3. Environmental transport, distribution, and transformation
1.4. Environmental levels and human exposure
1.5. Kinetics and metabolism
1.6. Effects on organisms in the environment
1.7. Effects on experimental animals
1.8. Effects on man
2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS
2.1. Identity
2.2. Physical and chemical properties
2.3. Conversion factors
2.4. Analytical methods
3. SOURCES IN THE ENVIRONMENT
3.1. Natural occurrence
3.2. Man-made sources
3.2.1. Production levels and processes
3.2.1.1 World production figures
3.2.1.2 Manufacturing processes
3.2.2. Uses
3.2.2.1 Aminoplastics (urea-formaldehyde resins and
melamine formaldehyde resins
3.2.2.2 Phenolic plastics (phenol formaldehyde resins)
3.2.2.3 Polyoxymethylene (polyacetal plastics)
3.2.2.4 Processing formaldehyde to other compounds
3.2.2.5 Medical and other uses
3.2.3. Sources of indoor environmental exposure
4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION
4.1. Transport, and distribution
4.2. Transformation
4.2.1. Special products of degradation under specific conditions
4.2.2. Microbial degradation
5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE
5.1. Environmental levels
5.1.1. Air
5.1.1.1 Air in the vicinity of industrial sources and
in urban communities
5.1.1.2 Emissions from industrial plants
5.1.1.3 Emissions from furnaces
5.1.1.4 Emissions from motor vehicles
5.1.2. Water
5.1.3. Soil
5.1.4. Food
5.2. Indoor air levels
5.2.1. Indoor exposure from particle boards
5.2.2. Indoor air pollution from urea-formaldehyde foam
insulation (UFFI)
5.2.3. Indoor air pollution from phenol-formaldehyde plastics
5.2.4. Exposure to indoor air containing cigarette smoke
5.3. General population exposure
5.3.1. Air
5.3.1.1 Smoking
5.3.2. Drinking-water
5.3.3. Food
5.3.4. Other routes of exposure
5.4. Occupational exposure
6. KINETICS AND METABOLISM
6.1. Absorption
6.1.1. Inhalation
6.1.1.1 Animal data
6.1.1.2 Human data
6.1.2. Dermal
6.1.3. Oral
6.2. Distribution
6.3. Metabolic transformation
6.4. Elimination and excretion
6.5. Retention and turnover
7. EFFECTS ON ORGANISMS IN THE ENVIRONMENT
7.1. Microorganisms
7.2. Aquatic organisms
7.3. Terrestrial organisms
7.4. Plants
8. EFFECTS ON EXPERIMENTAL ANIMALS AND IN VITRO TEST SYSTEMS
8.1. Skin and eye irritation; sensitization
8.2. Single exposures
8.3. Short-term exposures
8.3.1. Inhalation studies
8.3.2. Oral studies
8.4. Long-term exposure and carcinogenicity
8.4.1. Inhalation
8.4.2. Dermal studies
8.4.3. Oral studies
8.5. Mutagenicity and related end-points
8.6. Reproduction, embryotoxicity, and teratogenicity
8.7. Mechanisms of carcinogenicity
8.7.1. Reactions with macromolecules
8.7.2. Cytotoxicity and cell proliferation
9. EFFECTS ON MAN
9.1. Sources of exposure
9.2. General population exposure
9.2.1. Sensory effects
9.2.2. Toxic effects
9.2.3. Respiratory effects
9.2.4. Dermal, respiratory tract, and systemic sensitization
9.2.4.1 Mucosal effects
9.2.4.2 Skin effects
9.2.4.3 Respiratory tract sensitization
9.2.4.4 Systemic sensitization
9.2.4.4.1 Allergic reaction following the
dental use of paraformaldehyde
9.2.5. Skin irritation
9.2.6. Genotoxic effects
9.2.7. Effects on reproduction
9.2.8. Other observations in exposed populations
9.2.9. Carcinogenic effects
10. EVALUATION OF HUMAN HEALTH RISKS AND EFFECTS ON THE ENVIRONMENT
10.1. Evaluation of human health risks
10.2. Evaluation of effects on the environment
10.3. Conclusions
11. RECOMMENDATIONS
11.1. Recommendations for future research
11.2. Recommendations for preventive measures
12. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES
REFERENCES
WHO TASK GROUP ON ENVIRONMENTAL HEALTH CRITERIA FOR FORMALDEHYDE
Members
Professor O. Axelson, Department of Occupational Medicine, University
Hospital, Linköping, Sweden
Dr Birgitta Berglund, Department of Psychology, University of
Stockholm, Stockholm, Sweden
Professor D. Calamari, Institute of Agricultural Entomology, Faculty
of Agriculture, Milan, Italy ( Vice-Chairman )
Dr Ildiko Farkas, National Institute of Hygiene, Budapest, Hungary
Dr V.J. Feron, TNO-CIVO Toxicology and Nutrition Institute, AJ Zeist,
Netherlands
Dr O.J. Grundler, BASF AG, Ludwigshafen, Federal Republic of Germany
Professor J.M. Harrington, Institute of Occupational Health, University
of Birmingham, Birmingham, United Kingdom
Dr H.D. Heck, Chemical Industry Institute of Toxicology, Research
Triangle Park, USA
Dr R.F. Hertel, Fraunhofer Institute for Toxicology and Aerosol
Research, Hanover, Federal Republic of Germany ( Rapporteur )
Professor F. Klaschka, Department of Dermatology, Clinic and Polyclinic
in the Steglitz Clinic of the Free University of Berlin, Berlin
(West)
Dr Y. Kurokawa, Division of Toxicology, National Institute of Hygienic
Sciences, Tokyo, Japan
Dr Mathuros Ruchirawat, Department of Pharmacology, Faculty of Science,
Mahidol University, Bangkok, Thailand
Dr A. Schaich Freis, Danish National Institute of Occupational Health,
Copenhagen, Denmark
Dr A. Shaker, Environmental and Occupational Health Center, Ministry of
Health, Cairo, Egypt
Dr J.A.J. Stolwijk, Department of Epidemiology and Public Health, Yale
University School of Medicine, New Haven, USA ( Chairman )
Dr U. Thielebeule, Bezirks Hygiene Inspection, Rostock, German Demo-
cratic Republic
Observers
Dr J.C. Aubrun, (representing the European Council of Chemical Manu-
facturers) Courbevoie, France
Dr A. Basler, Federal Health Office, Berlin (West)
Dr J.-C. Berger, Health and Safety Directorate, Commission of the
European Communities, Luxembourg
Dr M.A. Cooke, University of Aston, Birmingham, United Kingdom
Mr W.R. Gaffey (representing Formaldehyde Institute), Department of
Medicine and Environmental Health, Monsanto Company, St. Louis, USA
Dr P. Messerer, BASF AG, Occupational Medicine and Health Protection,
Ludwigshafen, Federal Republic of Germany
Dr M.G. Penman (representing the European Chemical Industry Ecology
and Toxicology Centre), ICI, Central Toxicology Laboratory,
Macclesfield, United Kingdom
Dr N. Petri, BASF AG, Ludwigshafen, Federal Republic of Germany
Mr V. Quarg, Federal Ministry for Environment, Nature Conservation and
Nuclear Safety, Bonn, Federal Republic of Germany
Dr A.G. Smith (representing the European Chemical Industry Ecology and
Toxicology Centre), Ciba Geigy (UK), Macclesfield, United Kingdom
Dr K. Ulm, Institute for Medical Statistics and Epidemiology of the
Technical University of Munich, Munich, Federal Republic of Germany
Dr G. Vollmer, Federal Ministry for Environment, Nature Conservation
and Nuclear Safety, Bonn, Federal Republic of Germany
Secretariat
Dr D. Kello, Environmental Health Division, World Health Organization,
Regional Office for Europe, Copenhagen, Denmark
Dr E. Smith, International Programme on Chemical Safety, World Health
Organization, Geneva, Switzerland
Dr Linda Shuker, Division on Environmental Carcinogenesis, Inter-
national Agency for Research on Cancer, Lyons, France
NOTE TO READERS OF THE CRITERIA DOCUMENTS
Every effort has been made to present information in the criteria
documents as accurately as possible without unduly delaying their pub-
lication. In the interest of all users of the environmental health cri-
teria documents, readers are kindly requested to communicate any errors
that may have occurred to the Manager of the International Programme on
Chemical Safety, World Health Organization, Geneva, Switzerland, in
order that they may be included in corrigenda, which will appear in
subsequent volumes.
* * *
A detailed data profile and a legal file can be obtained from the
International Register of Potentially Toxic Chemicals, Palais des
Nations, 1211 Geneva 10, Switzerland (Telephone no. 7988400 -
7985850).
ENVIRONMENTAL HEALTH CRITERIA FOR FORMALDEHYDE
A WHO Task Group on Environmental Health Criteria for Formaldehyde
met at the Fraunhofer Institute for Toxicology and Aerosol Research,
Hanover, Federal Republic of Germany, from 9 to 13 November, 1987.
Professor U. Mohr opened the meeting and welcomed the members on behalf
of the host Institute, and Dr G. Vollmer spoke on behalf of the Federal
Government, which sponsored the meeting. Dr D. Kello, opened the meet-
ing on behalf of the Director-General, World Health Organization and
Dr E. Smith addressed the meeting on behalf of the three cooperating
organizations of the IPCS (UNEP/ILO/WHO). The Task Group reviewed and
revised the draft criteria document and made an evaluation of the risks
for human health and the environment of exposure to formaldehyde.
The drafts of this document were prepared by DR R.F. HERTEL and
DR G. ROSNER of the Fraunhofer Institute for Toxicology and Aerosol
Research, Hanover, Federal Republic of Germany. Available international
and national reviews of formaldehyde were consulted during the
preparation of the criteria document and are listed in the Appendix.
Dr E. Smith of the IPCS Central Unit was responsible for the overall
scientific contents of the document and Mrs M.O. Head of Oxford for the
editing.
The efforts of all who helped in the preparation and finalization
of the document are gratefully acknowledged.
* * *
Partial financial support for the publication of this criteria
document was kindly provided by the United States Department of Health
and Human Services, through a contract from the National Institute of
Environmental Health Sciences, Research Triangle Park, North Carolina,
USA - a WHO Collaborating Centre for Environmental Health Effects. The
United Kingdom Department of Health and Social Security also generously
contributed to the costs of printing.
1. SUMMARY AND CONCLUSIONS
1.1 Physical and Chemical Properties, and Analytical Methods
Formaldehyde is a flammable, colourless and readily polymerized gas
at ambient temperatures. The most common commercially available form is
a 30-50% aqueous solution. Formaldehyde is readily soluble in water,
alcohols, and other polar solvents, but has a low degree of solubility
in non-polar fluids.
Methanol or other substances are usually added to the solutions as
stabilizers to reduce intrinsic polymerization.
Formaldehyde decomposes at 150 °C into methanol and carbon monox-
ide; in general it is highly reactive with other chemicals. In sun-
light, it is readily photo-oxidized to carbon dioxide. It has a very
low n -octanol/water partition coefficient as well as a low soil-
absorption coefficient. The Henry constant is relatively high at
0.02 Pa x m3/mol.
Chemical analysis for formaldehyde involves direct extraction from
solid and liquid samples while absorption and/or concentration by ac-
tive (filtration) or passive (diffusion) sampling is necessary for air
samples. A variety of absorbants is available. The most widely used
methods of analysis are based on photometric determination. Low concen-
trations in air can be detected, after appropriate absorption, by means
of high performance liquid chromatography.
1.2 Sources of Human and Environmental Exposure
Formaldehyde is present in the environment as a result of natural
processes and from man-made sources. It is formed in large quantities
in the troposphere by the oxidation of hydrocarbons. Minor natural
sources include the decomposition of plant residues and the transform-
ation of various chemicals emitted by foliage.
Formaldehyde is produced industrially in large quantities and used
in many applications. Two other important man-made sources are automo-
tive exhaust from engines without catalytic converters, and residues,
emissions, or wastes produced during the manufacture of formaldehyde or
by materials derived from, or treated with it.
It has been calculated that the average rate of global production
from methane in the troposphere is of the order of 4 x 1011 kg/year,
while the total industrial production in recent years has been about
3.5 x 109 kg/year; the emission from automotive engines has not been
quantifiable on a global basis.
Formaldehyde has a variety of uses in many industries, it has medi-
cal applications as a sterilant and is used as a preservative in con-
sumer products, such as food, cosmetics, and household cleaning
agents.
One of the most common uses is in urea-formaldehyde and melamine-
formaldehyde resins. Urea-formaldehyde foam is used to insulate
buildings (UFFI); it can continue to emit formaldehyde after instal-
lation or constituting a source of persistent emission. Phenolic plas-
tics and polyacetal plastics are also important fields of application,
but are not expected to release formaldehyde.
There are several indoor environmental sources that can result in
human exposure including cigarettes and tobacco products, furniture
containing formaldehyde-based resins, building materials containing
urea-formaldehyde resins, adhesives containing formaldehyde used for
plastic surfaces and parquet, carpets, paints, disinfectants, gas
cookers, and open fireplaces.
Indoor areas of special importance are hospitals and scientific
facilities where formaldehyde is used as a sterilizing and preserving
agent, and living spaces, such as schools, kindergartens, and mobile
homes or apartments where there may be uncontrolled emissions of
formaldehyde from tobacco smoking, building materials, and furniture.
1.3 Environmental Transport, Distribution, and Transformation
Air is the most relevant compartment in the formaldehyde cycle,
most of the production and/or emissions, and degradation processes
occurring in the atmosphere.
Photolysis and reaction with hydroxyl radicals rapidly remove
formaldehyde from the atmosphere. The calculated half-life of each
process is a matter of hours, according to environmental conditions.
Transport of formaldehyde over distances is probably not of great
importance, nevertheless some organic compounds (air pollutants or
natural) from which formaldehyde can be derived are more stable and can
contribute to the formation of formaldehyde over considerable dis-
tances. The compound can be dissolved in the atmosphere in cloud and
rainwater and can be adsorbed as an atmospheric aerosol.
The value of the Henry constant suggests that formaldehyde in
aqueous solution is less volatile than water and that volatilization
from an aquatic environment is not expected under normal environmental
conditions. The high water solubility and the low n -octanol/water par-
tition coefficient suggest that adsorption on suspended solids and
partition in sediments is not significant. In water, formaldehyde is
rapidly (days) biodegraded by several species of microorganisms, pro-
vided the concentration is not too high. Formaldehyde is also readily
biodegradable in the soil. Because the soil adsorption coefficient is
very low, leaching occurs easily and mobility in soil is very high.
As it has a low n -octanol-water partition coefficient (log Pow),
formaldehyde is not be expected to bioaccumulate in aquatic organisms.
Furthermore, aquatic organisms are able to metabolize and transform it
through various metabolic pathways.
1.4 Environmental Levels and Human Exposure
Air concentrations of formaldehyde, near the ground in coastal,
mountain, or oceanic areas, ranged from 0.05 to 14.7 µg/m3, and the
majority of concentrations were within the range 0.1-2.7 µg/m3. In
the presence of man-made inputs, but away from any industrial
plants, mean values ranged from 7 to 12 µg/m3 with a few peaks up to
60-90 µg/m3. Data from different parts of the world were in good
agreement.
Rain water contains 110-174 µg/litre with peaks as high as
310-1380 µg/litre.
Emissions of formaldehyde from industrial processes vary widely
according to the types of industry. A considerable amount of formalde-
hyde comes from the exhaust emissions of motor vehicles, but this
varies greatly according to country and the grade of fuel.
There is some natural formaldehyde in raw food, levels ranging from
1 mg/kg up to 90 mg/kg, and accidental contamination of food may occur
through fumigation, the use of formaldehyde as a preservative, or
through cooking.
Tobacco smoke as well as urea-formaldehyde foam insulation and
formaldehyde-containing disinfectants are all important sources of
indoor formaldehyde.
Indoor air levels (non-workplace), measured in various countries,
depended on several factors, but mainly on the age of the building and
the building materials, the type of construction, and the ventilation.
They varied widely with different situations, but most ranged from a
minimum of 10 µg/m3 up to a maximum of 4000 µg/m3. In some cases,
low values were found in rooms with substantial sources of formaldehyde
emission. Disinfection of areas of hospitals produced the highest
levels, up to 20 000 µg/m3, but the personnel carrying out disin-
fection wear protective equipment and the areas are not occupied until
formaldehyde levels have fallen to 1.2 mg/m3 (1 ppm) and below. Levels
in rooms in which there is tobacco smoking can exceed 100 µg/m3.
The contributions of various atmospheric environments to the aver-
age human daily intake has been calculated to be 0.02 mg/day for out-
door air, 0.5-2 mg/day for indoor conventional buildings, < 1-10 mg/day
for buildings with sources of formaldehyde, 0.2-0.8 mg/day for work
places without occupational use of formaldehyde, 4 mg/day for work
places using formaldehyde, and 0-1 mg/day for environmental tobacco
smoke. Smoking 20 cigarettes per day corresponds to an intake of
1 mg/day through inhalation.
The formaldehyde concentration in drinking-water is generally
about 0.1 mg/litre resulting in a mean daily intake of 0.2 mg/day. The
quantity of formaldehyde ingested in food depends on the composition of
the meal and, for an average adult, may range from 1.5 to 14 mg/day.
1.5 Kinetics and Metabolism
Formaldehyde is readily absorbed in the respiratory and gastro-
intestinal tracts. Dermal absorption of formaldehyde appears to be very
slight. Increases in blood concentrations of formaldehyde were not de-
tected in rats or human beings exposed to formaldehyde through inha-
lation, because of rapid metabolism.
The metabolites of formaldehyde are incorporated into macromol-
ecules via one-carbon pathways or are eliminated in the expired air
(CO2) and urine. Formaldehyde that escapes metabolism can react with
macromolecules at the site of entry. DNA-protein cross-links have been
detected in tissues exposed directly to formaldehyde, but not in
tissues remote from the absorption site.
1.6 Effects on Organisms in the Environment
Formaldehyde is used as a disinfectant to kill viruses, bacteria,
fungi, and parasites, but it is only effective at relatively high
concentrations.
Algae, protozoa, and other unicellular organisms are relatively
sensitive to formaldehyde with acute lethal concentrations ranging
from 0.3 to 22 mg/litre. Aquatic invertebrates showed a wide range of
responses; some crustaceans are the most sensitive with median effec-
tive concentration (EC50) values ranging from 0.4 to 20 mg/litre. In
96-h tests on several fish species, the LC50 of formaldehyde for
adults ranged from a minimum of about 10 mg/litre to a maximum of sev-
eral hundred mg/litre; most species showed LC50 values in the range of
50-100 mg/litre. The responses of various species of amphibians are
similar to those of fish with median acute lethal concentrations
(LC50) ranging from 10 to 20 mg/litre for a 72-h exposure.
No data are available on long-term aquatic studies.
Eggs and larvae of some cattle parasites were killed by formal-
dehyde solution (1-5%) and some nematodes by a 37% solution, whereas
other nematodes were unaffected. In ruminant mammals, formaldehyde
protects dietary protein from microbial proteolysis in the rumen and
increases the efficiency of utilization of amino acids.
Few data are available on the effects of formaldehyde on plants.
However, from the agricultural use of urea-formaldehyde fertilizers, it
appears that, at recommended concentrations, formaldehyde does not
alter nitrogen and carbohydrate metabolism in plants, but that high
doses have negative effects on soil metabolism. Formaldehyde impairs
pollen germination.
1.7 Effects on Experimental Animals
Acute inhalation exposure of rats and mice to formaldehyde at very
high concentrations (120 mg/m3) produced salivation, dyspnoea,
vomiting, spasms, and death. At a concentration of 1.2 mg/m3, eye
irritation, decreased respiratory rate, increased airway resistance,
and decreased compliance appeared. Mice were more sensitive than
rats.
Short-term, repeated exposures (7-25 mg/m3) of rats produced
histological changes in the nasal epithelium, such as cell degener-
ation, inflammation, necrosis, squamous metaplasia, and increased cell
proliferation.
There is growing evidence that it is concentration rather than dose
that determines the cytotoxic effects of formaldehyde on the nasal
mucosa of rats; concentrations below 1 mg/m3 do not lead to cell
damage and hyperplasia.
Dose-related lesions observed in long-term, repeated inhalation
exposure (2.4, 6.7, or 17.2 mg/m3) were dysplasia and squamous meta-
plasia of the respiratory and olfactory epithelia, which regressed to
some extent after cessation of exposure.
Formaldehyde produced nasal squamous cell carcinomas in rats
exposed to high concentrations (17.2 mg/m3), which also caused severe
tissue damage. The concentration - response curve was extremely non-
linear with a disproportionate increase in tumour incidence at higher
concentrations. A low, but not statistically significant, incidence of
nasal tumours occurred at 6.7 mg/m3. No tumours were found at other
sites. Mice developed squamous cell carcinomas of the nasal cavity with
long-term exposure to 17.2 mg/m3, but this finding was not statisti-
cally significant. No tumours were found at other sites. No tumours
were found in hamsters.
Long-term oral administration of formaldehyde (0.02-5% in the
drinking-water) to rats was found to induce papillomas in the fore-
stomach.
Several skin initiation/promotion studies with formaldehyde did not
produce evidence of skin carcinogenicity in mice; the results with
respect to promotion were either negative or inconclusive.
1.8 Effects on Man
Formaldehyde has a pungent odour detectable at low concentrations,
and its vapour and solutions are known skin and eye irritants in human
beings. The common effects of formaldehyde exposure are various symp-
toms caused by irritation of the mucosa in the eyes and upper airways.
In the non-industrial indoor environment, sensory reactions are typical
effects, but there are large individual differences in the normal popu-
lation and between hyperreactive and sensitized people.
There are a few case reports of asthma-like symptoms caused by
formaldehyde, but none of these demonstrated a sensitization effect
(neither Type I nor Type IV) and the symptoms were considered to be due
to irritation. Skin sensitization is induced only by direct skin
contact with formaldehyde solutions in concentrations higher than
20 g/litre (2%). The lowest patch test challenge concentration in an
aqueous solution reported to produce a reaction in sensitized persons
was 0.05% formaldehyde.
The available human evidence indicates that formaldehyde does not
have a high carcinogenic potential. While some studies have indicated
an excess of cancer in exposed individuals or populations, only nasal
or nasopharyngeal tumours are likely to be causally related to formal-
dehyde exposure.
Formaldehyde does not have any adverse effects on reproduction and
is not teratogenic.
Formaldehyde in vitro interferes with DNA repair in human cells,
but there are no data relating to mutagenic outcomes.
2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS
2.1 Identity
Chemical formula: CH2O [HCHO]
Chemical structure: H
|
C = O
|
H
CAS registry number: 50-00-0
RTECS registry number: LP 8925000
UN number: 1198, 2209, 2213
EC numbers: 605-001-01 (solution 5% to < 25%)
605-001-02 (solution 1% to < 5%)
605-001-005 (solution > 25%)
IUPAC name: Methanal
Common synonyms: formaldehyde, methanal, methylene oxide,
oxymethylene, methylaldehyde, oxomethane
Common names for solutions
of formaldehyde: Formalin, Formol
Formaldehyde is a colourless gas at normal temperature and press-
ure, with a relative molecular mass of 30.03.
The most common commercially available form is a 30-50% aqueous
solution. Methanol or other substances are usually added to the sol-
ution as stabilizers to reduce intrinsic polymerization. The concen-
tration of methanol can be up to 15%. The concentration of other
stabilizers is of the order of several 100 mg/litre. Concentrated
liquid formaldehyde-water systems containing up to 95% formaldehyde are
obtainable, but the temperature necessary to maintain solution and
prevent separation of polymer increases from around room temperature to
120 °C as the solution concentration increases.
In solid form, formaldehyde is marketed as trioxane (CH2O)3,
and its polymer, paraformaldehyde, with 8-100 units of formaldehyde.
Paraformaldehyde has become technologically important.
2.2 Physical and Chemical Properties
Formaldehyde is a flammable, colourless, reactive, and readily
polymerized gas at normal temperature. The heat of combustion for
formaldehyde gas is 4.47 Kcal per gram. It forms explosive mixtures
with air and oxygen at atmospheric pressure. Flammability is reported
to range from 12.5 to 80 volume %, a 65-70% formaldehyde-air mixture
being the most readily flammable.
Formaldehyde is present in aqueous solutions as a hydrate and tends
to polymerize. At room temperature and a formaldehyde content of 30%
and more, the polymers precipitate and render the solution turbid.
Formaldehyde decomposes into methanol and carbon monoxide at
temperatures above 150 °C, although uncatalysed decomposition is slow
below 300 °C.
Under atmospheric conditions, formaldehyde is readily photo-
oxidized in sunlight to carbon dioxide. It reacts relatively quickly
with trace substances and pollutants in the air so that its half-life
in urban air, under the influence of sunlight, is short. In the absence
of nitrogen dioxide, the half-life of formaldehyde is approximately
50 min during the daytime; in the presence of nitrogen dioxide, this
drops to about 35 min (Bufalini et al., 1972).
Some physical and chemical properties of formaldehyde are presented
in Table 1.
Table 1. Physical and chemical properties of formaldehydea
------------------------------------------------------------
Relative molecular mass 30.03
Relative gas density (air = 1) 1.04
Melting point (°C) -118b
Boiling point (°C) -19.2b
Explosivity range in air (vol %) 7-73
(g/m3) 87-910
n -octanol/water partition -1
coefficient) (log Pow)
Specific reaction rate (k) with 15.10-18 m3/mol x s
OH radical (k OH )
Distribution water/air: Henry 0.02 Pa. m3/mol
constant (H)
Vapour pressure 101.3 kPa at -19 °C
52.6 kPa at -33 °C
------------------------------------------------------------
a Modified from: BGA (1985).
b From: Diem & Hilt (1976) and IARC (1982).
From: Neumüller (1981) and Windholz (1983).
2.3 Conversion Factors
1 ppm formaldehyde = 1.2 mg/m3 at 25 °C, 1066 mbar
1 mg formaldehyde/m3 = 0.83 ppm
A number of other conversion factors have been cited but, for this
draft, 0.83 has been used.
2.4 Analytical Methods
The most widely used methods for the determination of formaldehyde
are based on photometric measurements. Methods for the sampling and
determination are summarized in Table 2. The type of sampling depends
on the medium in which the formaldehyde is to be determined.
Direct and indirect methods can be used for sampling formaldehyde
in air. Indirect sampling (by means of a grab sample) is used when
formaldehyde is present in extremely low concentrations or where sam-
pling sites are removed from analytical laboratories. However, lack of
preconcentration means that a very sensitive analytical technique is
needed and there may also be absorption on the wall of the collecting
container. Alternatively, the sample may be preconcentrated by passing
air (active sampling) through an absorbing liquid. The collection ef-
ficiency of some liquids is reported in NRC (1981):
Water 80-85% (85% with ice bath)
1% aqueous bisulfite 94-100% (with ice bath)
3-methyl-2-benzothiazolene
hydrazine (MBTH) 84-92%
Chromotropic acid in concen-
trated sulfuric acid 99%
Concentrated sulfuric acid 99%
Formaldehyde in air may be collected in an absorbing medium by dif-
fusion (passive sampling). Aqueous or 50% 1-propanol solutions are used
for formaldehyde sampling. For active sampling, aqueous solutions and
solutions containing sulfite, 3-methyl-2-benzothiazolonehydrazone
(MBTH), chromotropic acid, or 2,4-dinitrophenylhydrazine (DNPH) are
generally used as the absorbing solution (Stern, 1976). For passive
sampling, sodium bisulfite (Kennedy & Hull, 1986), triethanolamine
(Prescher & Schönbude, 1983), and DNPH (Geisling et al., 1982) are used
and sorbents such as silica gel, aluminium oxide, and activated carbon,
sometimes specially pretreated, may be useful for taking samples at the
work place (DFG, 1982).
Table 2. Sampling and analytical methods for formaldehydea
--------------------------------------------------------------------------------------------------------
Method Sampling Analysis Sensitivity mg/litre (ppm) Interferences
15-min long-term
--------------------------------------------------------------------------------------------------------
Chromotropic acid: midget spectrophotometry 0.19 (0.16) 0.05 (0.04) phenol, other
NIOSH 3500 impinger (1 h) organic substances
Paraosaniline midget spectrophotometry 0.02 (0.02) 0.0006 (0.0005) sulfur dioxide
(original) impinger (8 h)
Paraosaniline midget spectrophotometry 0.05 (0.045) 0.0012 (0.001) sulfur dioxide
(modified) impinger (8 h)
Paraosaniline continuous colorimetric 0.06 (0.05) NA sulfur dioxide
(TGM-555)
MBTH absorber spectrophotometry 0.12 (0.10) 0.0036 (0.003)
(8 h)
Acetylacetone midget spectrophotometry 0.12 (0.10) --- other aldehydes,
spectrophotometric impinger amines, Sulfur
dioxide
Acetylacetone midget fluorimetry 0.05 (0.04) --- other aldehydes,
fluorimetric impinger amines, Sulfur
dioxide
2.4-DNPH aqueous midget HPLC 0.00007 0.000018 (0.000015)
ethanol impinger (0.00006) (1 h)
2.4-DNPH coated adsorbent HPLC 1.58 (1.32) 0.12 (0.10)
adsorbent tube (3 h)
NIOSH 3501 midget polarography 1.94 (1.62) 0.32 (0.27) other aldehydes
impinger (1.5 h)
OSHA acidic midget polarography 0.12 (0.10) 0.012 (0.01) acetaldehyde
hydrazine impinger (2.5 h)
-------------------------------------------------------------------------------------------------------
Table 2 (contd).
-------------------------------------------------------------------------------------------------------
Method Sampling Analysis Sensitivity mg/litre (ppm) Interferences
15-min long-term
-------------------------------------------------------------------------------------------------------
NIOSH 2502 reactive gas chromatography 9.38 (7.82) 0.6 (0.5)
adsorbent (4 h)
MIRAN continuous infrared 0.5 (0.4) NA multiple
Draeger reactive visual 0.6 (0.5) NA
adsorbent
Passive reactive spectrophotometry 3.84 (3.2) 0.12 (0.1)
monitor 3M adsorbent (CA) (8 h)
DuPont reactive spectrophotometry 9.6 (8) 0.3 (0.25)
adsorbent (CA) (8 h)
Air Quality reactive spectrophotometry 8.04 (6.7) 0.25 (0.21)
Research adsorbent (CA) (8 h)
Envirotech moist spectrophotometry 0.86 (0.72) 0.07 (0.06) other aldehydes
adsorbent (PUR) (8 h)
-------------------------------------------------------------------------------------------------------
a Modified from: Consensus Workshop on Formaldehyde (1984).
In 1981, the US National Institute of Occupational Safety and
Health (NIOSH) developed a solid-sorbent sampling method in which
samples collected can be stored for at least 14 days, at room tempera-
ture, before analysis, without loss of the analyte (Blade, 1983).
A method for the specific and sensitive determination of formal-
dehyde and other aldehydes and ketones in air has been described by
Binding et al. (1986). The specificity is based on subsequent high per-
formance liquid chromatographic separation. In air samples of 5 litres,
the detection limit is 0.05 ml/m3. The method is suitable for deter-
mining 5-min short-term values, as well as for continuous sampling over
a whole work shift.
A sensitive method for the determination of formaldehyde is based
on the Hantzsch reaction between acetylacetone (2,4-pentanedione) am-
monia and formaldehyde to form 3,5-diacetyl-1,4-dihydrolutidine. For-
maldehyde concentration can be determined colorimetrically (Nash, 1953)
or, more sensitively, by fluorimetry (Belman, 1963). The method is sub-
ject to interference by oxides of nitrogen, sulfur dioxide and ozone
but is less subject to interference by phenol than the chromotropic
acid method.
Photometric assay, using the sulfite-pararosaniline or the chromo-
tropic acid method, is usually applied to determine formaldehyde in
air. Automated analytical equipment has been developed.
Suitable analytical methods for monitoring air in the work-place
environment have been developed and recommended by the German Research
Society, DFG (1982) and by NIOSH (1984).
Menzel et al. (1981) described a special continuously-operating
measuring device, developed for determining formaldehyde in particle
boards for classification purposes; equipment for continuous measure-
ments using the pararosaniline method is available (Lyles et al.,
1965).
A simple colour reaction for the identification of urea formalde-
hyde resins and diisocyanates, carried out on the surface of wood-based
panels, has been described by Schriever (1981). This is based on the
reaction with p -dimethyl-aminocinnamaldehyde (DACA), resulting in a
red colour for both the resins and diisocyanates. The reaction of
purpald with formaldehyde is used to distinguish between urea formalde-
hyde resins and diisocyanates and it is possible to identify diiso-
cyanates when mixed with urea formaldehyde resins.
Water sampling may be by means of grab samples. Where water or
individual effluents are not homogeneous several subsamples may be
collected at different times from different sampling locations and
combined for analysis. If sample storage is necessary it should be
frozen or at least kept at 4 °C to prevent biological or chemical
degradation of formaldehyde. An organic solvent is used for extraction
of formaldehyde prior to analysis.
Concentrations of formaldehyde in the air in the range of
0.05-40 mg/m3 can be determined by the use of gas-detector tubes which
contain a colour reagent (Leichnitz, 1985). They cannot be relied upon
in the presence of other substances, e.g., tobacco smoke or below a
concentration of 0.05 mg/m3.
Formaldehyde can be extracted from foods using a solvent, such as
isopetane, or by steam distillation and extraction with ether. Before
extraction foodstuffs may be pulverized or homogenized.
The Association of Official Analytical Chemists (AOAC, 1984)
recommends the Helmer-Fulton Test (registration No. 20.081) for the
determination of formaldehyde in food and a spectrophotometric method
(Nash's reagent B; registry no. 31203) for the determination of formal-
dehyde in maple syrup.
3. SOURCES IN THE ENVIRONMENT
3.1 Natural Occurrence
Formaldehyde is naturally formed in the troposphere during the
oxidation of hydrocarbons. These react with OH radicals and ozone to
form formaldehyde and/or other aldehydes as intermediates in a series
of reactions that ultimately lead to the formation of carbon monoxide
and dioxide, hydrogen, and water (Zimmermann et al., 1978; Calvert,
1980).
Of the hydrocarbons found in the troposphere, methane occurs in the
highest concentration (1.18 mg/m3) in the northern hemisphere. Thus,
it provides the single most important source of formaldehyde (Lowe et
al., 1981).
Terpenes and isoprene, emitted by foliage, react with the OH radi-
cals, forming formaldehyde as an intermediate product (Zimmermann et
al., 1978). Because of their short life-times, this potentially impor-
tant source of formaldehyde is only important in the vicinity of vege-
tation (Lowe et al., 1981). The processes of formaldehyde formation and
degradation are discussed in section 4.
Formaldehyde is one of the volatile compounds formed in the early
stages of decomposition of plant residues in the soil (Berestetskii et
al., 1981).
3.2. Man-Made Sources
The most important man-made source of formaldehyde is automotive
exhaust from engines not fitted with catalytic converters (Berglund et
al., 1984; Guicherit & Schulting, 1985).
3.2.1 Production levels and processes
Table 3. World production figures for formaldehyde
--------------------------------------------------------
Year Area Quantity
(million kg)
--------------------------------------------------------
1978 USA, 16 companies 1073
1978 Canada, 4 companies 88
1979 USA, 16 companies 1003
1983 USA 905
1983 Germany, Federal Republic of,
11 companies 534
1983 Japan, 24 companies 403
1983 Major producing countries total 3200
1984 Major producing countries total 5780
1985 USA, 13 companies 941
--------------------------------------------------------
3.2.1.1 World production figures
The total production figures for formaldehyde are calculated on a
100% formaldehyde basis, though a variety of concentrations and forms
are produced. In 1984, the overall production capacity of major indus-
trial countries was approximately 5780 million kg/year (European Eco-
nomic Community 1700 kg/year, other Western European countries 530, USA
1440, Japan 640, other Asian countries and Australia 1240, Latin
America 230). Formaldehyde is also produced in Africa and the USSR. No
production figures for formaldehyde are available for eastern industri-
alized countries (Izmerov, 1982). Table 3 shows actual production fig-
ures for some western industrialized countries.
3.2.1.2 Manufacturing processes
Formaldehyde is produced by oxidizing methanol using two dif-
ferent procedures: (a) oxidation with silver crystals or silver
nets at 600-720 °C; and (b) oxidation with iron molybdenum oxides at
270-380 °C. Formaldehyde can be produced as a by-product of hydrocarbon
oxidation processes (Walker, 1975), but this method is not used commer-
cially.
Formaldehyde is an inexpensive starting material for a number of
chemical reactions, and a large number of products are made using for-
maldehyde as a base. Thus, it is important in the chemical industry.
3.2.2 Uses
Products manufactured using formaldehyde as an intermediate product
are listed in Table 4.
In animal nutrition, formaldehyde is used to protect dietary pro-
tein in ruminants (section 7.3). In the USA, formaldehyde is used as a
food additive to improve the handling characteristics of animal fat and
oilseed cattle food mixtures by producing a dry free-flowing product
(US FDA, 1980). Urea formaldehyde fertilizer is used in farming as a
source of nitrogen to improve the biological activity of the soil
(section 7.1).
3.2.2.1 Aminoplastics (urea formaldehyde resins and melamine formalde-
hyde resins)
Reaction of formaldehyde with urea or melamine yields urea formal-
dehyde (UF) or melamine formaldehyde (MF) (condensation process). These
synthetic resins are then delivered in solution or powder form at vari-
ous concentrations for further processing.
Table 4. Products produced with formaldehyde as a compounda
-----------------------------------------------------------------------------
Intermediate product Product
-----------------------------------------------------------------------------
urea formaldehyde resins particleboard, fibreboard, plywood,
paper treatment, textile treatment,
moulding compounds, surface coatings,
foam
phenolic resins plywood adhesives, insulation,
foundry binders
melamine resins surface coatings, moulding compounds,
laminates, wood adhesives
hexamethylenetetramine phenolic thermosetting, resin curing
agents, explosives
trimethylolpropane urethanes, lubricants, alkyd resins,
multifunctional acrylates
1,4-butanediol tetrahydrofuran, butyrolactone,
polybutylene terephthalate
polyacetal resins auto applications, plumbing components
pentaerythritol alkyd resins, synthetic lubricants,
tall oil esters, foundry resins,
explosives
urea formaldehyde concentrates controlled release fertilizers
-----------------------------------------------------------------------------
a From: Archibald (1982).
In the Federal Republic of Germany, about 70% of the total amount
of aminoplastics produced, i.e., 170 000 tonnes of formaldehyde per
annum, is used as glue in the manufacture of particle boards. These
boards are mostly manufactured from urea formaldehyde resins, the
water resistance of which is less than that of other resins, but is
sufficient for use in enclosed areas. About 10% of the aminoplastic
glues used are melamine-urea-formaldehyde resins, i.e., products where
melamine and urea are co-condensed with formaldehyde. Melamine resins
are more damp-proof than urea resins, but they are also more expens-
ive.
Formaldehyde can be released from such wood products over a long
period, even years, at a continuously declining rate. This occurs es-
pecially if the particle board material has become wet due to careless
handling, e.g., in construction work. The emission is composed of the
excess of formaldehyde used during actual production of the wood prod-
ucts and that produced by hydrolytic cleavage of unreacted methylol
groups in the resins. Melamine formaldehyde resins are generally more
stable and the amounts of formaldehyde emitted from them are much lower
(Deppe, 1982).
Aminoplastics are also used as glue for plywood and in the manufac-
ture of furniture. Paper saturated with aminoplastics and with a high
melamine-formaldehyde-resin content is used to coat surfaces of par-
ticle boards. Aminoplastics are used to increase the wet strength of
certain products in the paper industry.
Urea formaldehyde resins are used as urea formaldehyde foam insu-
lation (UFFI), or as reinforcing foams in the insulation of buildings
and in mining, where hollow areas are filled with foam. UFFI is pro-
duced by the aeration of a mixture of urea formaldehyde resin and an
aqueous surfactant solution containing a phosphoric acid curing cata-
lyst (Meek et al., 1985). This type of foam can emit formaldehyde, even
after completion of work, depending on factors such as process and
installation, age of building materials, temperature, and humidity.
Condensed aminoplastics of very low relative molecular mass serve
as textile treatments to make cotton and fabrics containing synthetic
fibres creaseproof and permanently pressed. In the USA, it is estimated
(CPSC, 1979) that approximately 85% of all fabrics used in the clothing
industry have been treated in this way. Extremely stable aminoplastics
are used in order to ensure that they will not degrade during the life-
time of the articles. Formaldehyde concentrations ranging from 1 to
3000 mg/kg were found in such fabrics in the early years of this type
of use (Schorr et al., 1974). However, residues of free formaldehyde
from the manufacturing process can largely be removed by heat treatment
with washing during the textile finishing process. In the last 10
years, the processing of finishing agents in the textile industry has
improved and textiles treated with formaldehyde-containing finishing
agents contain very little free formaldehyde and cannot cause allergic
contact dermatitis (Bille, 1981).
Compounds similar to those used in finishing textiles are used in
the tanning of leather. Another field of application is for amino-
plastics mixed with rock or wood dust, fibres, or synthetic pulp in
hard materials manufactured by hot moulding. They are used in electri-
cal engineering, e.g., in light switches, sockets, and in parts of
electrical motors; in mechanical engineering; in the motor-vehicle
industry; and for household articles, e.g., camping dishes, parts of
electrical household appliances, lamps, and plumbing components.
Aminoplastics are used in the paint industry as carriers in
binders for special types of lacquer and paint, e.g., for cars. In
agriculture, they are used as preservatives. They are also used in
carpet-cleaning agents in the form of foam resin.
The fields of application of aminoplastics in the Federal Republic
of Germany are given in Tables 5 and 6.
3.2.2.2 Phenolic plastics (phenol formaldehyde resins)
Phenolic plastics are synthetic resins in which formaldehyde is
condensed with phenols. Phenol, resorcinol, and cresols are among the
phenolic components. Owing to the stable binding of phenol and formal-
dehyde, formaldehyde should not be emitted from the final products made
of phenolic plastics, as long as there is no free formaldehyde
present.
As in the case of aminoplastics, the wood-working industry is a
major consumer.
Table 5. Uses of melamine formaldehyde resins in the Federal Republic of
Germany during 1981-82a
------------------------------------------------------------------
Area of use Proportion as Consumption
% of resin of formaldehyde
consumption (tonnes)
------------------------------------------------------------------
Adhesive resins for timber 30 12 000
products, especially particle
boards (adhesives)
Resin varnishes 36 14 500
Hardenable moulding material 10 4 000
for plastic products
Raw materials for paints 8 3 000
Paper and textile finishing 5 2 000
Other 11 4 500
------------------------------------------------------------------
a From: BASF (1984).
Other major areas of application are the production of hard
materials, similar to those produced from aminoplastics, as a moulding
material, and as a binder in enamel, paints, and lacquers.
Phenolic plastics are used as binders in the production of insu-
lating materials from rock wool or glass fibres, in brake linings,
abrasive materials, and moulded laminated plastics. They also serve as
binding agents for moulding sand in foundries. Fields of application of
phenolic plastics in the Federal Republic of Germany are listed in
Table 7.
Emissions of formaldehyde are produced when processing phenolic
plastics at high temperatures. Phenol and formaldehyde emissions during
moulding led to complaints in previous decades about annoying smells.
Now, resins have been improved to meet work-place environment standards
and emissions should not cause annoyance.
3.2.2.3 Polyoxymethylene (polyacetal plastics)
Polyoxymethylenes (POM) are another type of plastics produced by
polymerizing formaldehyde. Like the final products from phenolic plas-
tics, articles made of polyoxymethylene are not expected to emit
formaldehyde.
Polyoxymethylenes are harder, tougher, and longer-lasting than
other plastics and are used in many areas of application in which met-
allic materials were previously used. They are used in producing motor-
vehicle and machine parts that are subjected to mechanical or thermal
stress, parts for precision and communication engineering, parts for
household appliances, and plumbing fixtures.
Table 6. Uses of urea formaldehyde resins in the Federal Republic of
Germany during 1981-82a
------------------------------------------------------------------
Area of use Proportion as Consumption of
% of resin formaldehyde
consumption (tonnes)
------------------------------------------------------------------
Adhesive resins for timber 80 160 000
products, especially particle
boards (adhesives)
Paper finishing 4 8 000
Hardenable moulding material 4 8 000
for plastic products
Textile finishing 3 6 000
Resin varnishes for impregnating, 2 4 000
e.g., moulded, laminated plastics
Foam resins 2 4 000
for: building insulation 0.2
mining 1.0
amelioration 0.4
carpet-cleaning products 0.3
other purposes 0.1
Raw materials for paints 2 4 000
Binding agents for fibre 1 2 000
mats, etc.
Foundry resins 1 2 000
Other 1 2 000
------------------------------------------------------------------
a From: BASF (1984).
3.2.2.4 Processing formaldehyde to other compounds
Formaldehyde is an important raw material in the industrial syn-
thesis of a number of organic compounds.
In the Federal Republic of Germany during 1981-82, the chemical
industry processed 34% of all formaldehyde products to the following
derivative substances (BASF, 1984):
- 1,4 butane diol 10%
- pentaerythritol 6%
- methylenediphenyldiisocyanate 5%
- trimethylolpropane and neopentylglycol 4%
- hexamethylenetetramine 2%
- chelating agents (NTA, EDTA) 2%
- miscellaneous (e.g., dyes, dispersion, 5%
pesticides, perfumes, vitamins)
Table 7. Uses of phenolic plastic resins in the
Federal Republic of Germany during 1981-82a
------------------------------------------------------------------
Area of use Proportion as Consumption of
% of resin formaldehyde
consumption (tonnes)
------------------------------------------------------------------
Hardenable moulding material 23 9000
for plastic products
Adhesive resins for timber 20 8000
products, especially particle
boards (adhesives)
Binding agents for rock wool, 17 7000
glass wool, etc.
Raw materials for paints 14 5500
Foundry resins 7 3000
Resin varnishes for impregnating, 4 1500
e.g., moulded, laminated plastics
Abradant binders, e.g., for 3 1000
sandpaper
Binding agents for friction 3 1000
surfaces, e.g., brake linings
Rubber chemicals 2 1000
Other 7 3000
------------------------------------------------------------------
a From: BASF (1984).
3.2.2.5 Medical and other uses
The use of formaldehyde in medical and other fields is relatively
small (1.5% of the total production) compared with its use in the manu-
facture of synthetic resins and chemical compounds. However, its use in
these areas is of great significance for human beings, since it occurs
either as free formaldehyde and can therefore be easily liberated and
affect people (e.g., when used as a disinfectant) or it may reach many
people via various consumer goods, such as preservatives and cosmetics.
The use of formaldehyde for the preservation of organic material is of
historical importance.
Examples of fields of application are listed in Table 8.
Table 8. Use of products containing formaldehyde in medicinal
and other technical areasa
-------------------------------------------------------------------------
Area Use
-------------------------------------------------------------------------
Detergents and cleaning Preservative in soaps, detergents, cleaning
agents industry agents
Cosmetics industry Preservative in soaps, deodorants, shampoos,
etc; additive in nail hardeners and products
for oral hygiene
Sugar industry Infection inhibitor in producing juices
Medicine Disinfection, sterilization, preservation of
preparations
Petroleum industry Biocide in oil well-drilling fluids; auxiliary
agent in refining
Agriculture Preservation of grain, seed dressing, soil
disinfection, rot protection of feed, nitrogen
fertilizer in soils, protection of dietary
protein in ruminants (animal nutrition)
Rubber industry Biocide for latex; adhesive additive; anti-
oxidizer additive also for synthetic rubber
Metal industry Anti-corrosive agent; vehicle in vapour
depositing and electroplating processes
Leather industry Additive to tanning agents
Food industry Preservation of dried foods; disinfection of
containers; preservation of fish and certain
oils and fats; modifying starch for cold
swelling
Wood industry Preservative
Photographic industry Developing accelerator; hardener for gelatin
layers
-------------------------------------------------------------------------
a Modified from: BASF (1984).
(a) Disinfectants and sterilizing agents
At present, formaldehyde is the disinfectant with the broadest ef-
ficiency; its virucidal property makes it indispensable for disinfec-
tion in the clinical field. It is an important active substance in dis-
infectants that kill and inactivate microorganisms and are used in the
prevention and control of communicable diseases and hospital infections
(BGA, 1982). Agents containing formaldehyde are marketed as concen-
trated solutions and must be diluted appropriately by the user. These
concentrates usually contain 6-10% formaldehyde, occasionally up to
30%. The formaldehyde contents of the diluted mixtures lie between 0.3
and 0.5% and, in exceptional cases, 0.9%. Application of the solutions
is supposed to kill pathogenic organisms on the surfaces of objects.
The ensuing effect is proportional to the concentration of formal-
dehyde, length of application, and temperature (Spicher & Peters,
1981). The objects to be disinfected are either placed in the formal-
dehyde solution (e.g., disinfecting linen in washing machines) or wiped
and/or sprayed with the solutions. When disinfecting a room, a formal-
dehyde solution is either vaporized or atomized. Disinfecting in a
formaldehyde chamber and gas sterilization both work on a similar
principle, that is a mixture of formaldehyde and water vapour is pumped
into a special air-tight chamber in which the objects to be disinfected
or sterilized have been placed. This method is also used to disinfect
incubators for premature babies and haemodialysis equipment.
(b) Medicines
Pharmaceutical products containing formaldehyde are rarely used for
disinfecting the skin and mucous membranes, but formaldehyde is added
to pharmaceutical products as a preservative.
Root canal filling sealants containing paraformaldehyde are used in
dental surgery.
(c) Cosmetics
Formaldehyde is used as a preservative in cosmetics and in nail-
hardening agents. Traces can be found in cosmetics resulting from the
disinfecting of apparatus used in their manufacture. Furthermore, pro-
ducts containing formaldehyde are used for other purposes, e.g., anti-
perspirants and skin-hardening agents. The formaldehyde content of some
cosmetics has been reported to be up to 0.6% and is as high as 4.5% in
nail hardeners (Marzulli & Maibach, 1973; Consensus Workshop on Formal-
dehyde, 1984). Concentrations in dry-skin lotion, creme rinse, and
bubble bath oil are in the range of 0.4-0.6%. Present regulatory values
are given in section 11.
Formaldehyde is considered technically superior to a number of
other preservatives, especially in products with a high water content,
e.g., shampoos. As a preservative, formaldehyde also assures that the
product is germ-free, prevents microbial contamination during pro-
duction and packaging, multiplication of residual organisms during
storage, and re-contamination during use.
(d) Consumer goods and other products
The use of formaldehyde in consumer goods is intended to protect
the products from spoilage by microbial contamination.
It is used as a preservative in household cleaning agents, dish-
washing liquids, fabric softeners, shoe-care agents, car shampoos and
waxes, carpet cleaning agents, etc. As a rule, the formaldehyde concen-
tration is less than 1%. Disinfecting cleaning agents contain higher
concentrations (up to 7.5%) and are diluted before use.
Flooring adhesives contain formaldehyde. It is added to paper,
leather, dyes, wood preservatives, sealing agents for parquet floors,
as a preservative with fungicidal and bactericidal properties (see also
Table 4).
Formaldehyde is a component of reactive resins (urea formaldehyde
resins, melamine formaldehyde resins, phenol formaldehyde resins,
benzoguanomine formaldehyde, and polymers on a methyloacylamide and/or
methylomethacrylamide basis), which control the hardening properties of
lacquers and varnishes and are essential for the surface properties of
the treated products. The resins used for these purposes contain free
formaldehyde at concentrations of up to 3%, this means up to 0.3% in
ready-to-use varnishes (BASF, 1983). This free formaldehyde is emitted
during application. Thermal degradation of resins during the baking of
paints may cause additional emissions of formaldehyde.
3.2.3 Sources of indoor environmental exposure
The major man-made sources affecting human beings are in the indoor
environment. Primary sources include cigarette smoke, particle board
and plywood, furniture and fabrics, gases given off by heating systems,
and cooking.
Thus, the indoor levels of formaldehyde differ clearly from the
concentrations in the outdoor air. Indoor concentrations are influenced
by temperature, humidity, ventilation rate, age of the building, prod-
uct usage, presence of combustion sources, and the smoking habits of
occupants. When considering the indoor presence of formaldehyde, it is
necessary to differentiate between:
- Hospitals or other scientific facilities, where formaldehyde has to
be used as a disinfectant or preservative; and
- All other indoor areas, especially living spaces, schools, kinder-
gartens, and mobile homes where there may be uncontrolled emissions
of formaldehyde from sources such as smoking, building materials,
and furniture. This sector presents the specific problems in indoor
areas.
Possible sources of indoor formaldehyde emissions are:
- cigarettes and other tobacco products;
- particle boards;
- furniture; urea formaldehyde foam insulation (UFFI);
- gas cookers;
- open fireplaces;
- other building materials made with adhesives containing
formaldehyde, such as plastic surfaces and certain parquet
varnishes;
- carpeting, drapes, and curtains;
- paints, coatings, and wood preservatives; and
- disinfectants and sterilizing agents.
Other products containing formaldehyde do not noticeably contribute
to indoor exposure because of their stable formaldehyde binding, e.g.,
plastic articles made by moulding, or because of their low rate of
emission, e.g., cosmetics. Data are summarized in Tables 15 and 16
(section 5.2).
4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION
4.1 Transport and Distribution
The degradation of methane is a major source of the natural back-
ground concentration of formaldehyde in the atmosphere. Since methane
is widely distributed naturally and has a half-life of several years,
formaldehyde is formed on a global scale.
Fig. 1 provides a survey of processes that may contribute to for-
maldehyde concentrations in ambient air.
Formaldehyde is a highly reactive compound with a half-life in the
atmosphere of about 1-3 h in the sunlit troposphere at 30° N at mid-day
(Bufalini et al., 1972; Lowe & Schmidt, 1983). Therefore, transpor-
tation of formaldehyde over distances is probably not of great import-
ance.
The organic compounds from which formaldehyde is derived are usual-
ly much more stable. Thus, emissions of organic air pollutants can con-
tribute to the formation of formaldehyde over considerable distances.
Various photochemical models have also been used to predict formal-
dehyde distribution in the troposphere, but the computed values are
difficult to compare, because of the different assumptions used to
generate the models.
Lowe et al. (1981) estimated a chemical life-time for formaldehyde
using the following reactions for formaldehyde formation (Levy, 1971):
CH4 + OH -> CH3 + H2O (1)
CH3 + O2 + M -> CH3O2 + M (2)
CH3O2 + NO -> NO2 + CH3O (3)
CH3O + O2 -> HCHO + HO2 (4)
Wofsy et al. (1972) considered that reaction (3) was unlikely and
suggested that methyl hydroperoxide (CH3OOH) could be an intermediate
in the reaction series producing formaldehyde.
CH3O2 + HO2 -> CH3OOH + O2 (5)
CH3OOH + hv -> CH3O + OH (6)
CH3O + O2 -> HCHO + HO2 (7)
For the purposes of estimating a chemical life-time for formal-
dehyde in the troposphere, reactions (1)-(4) are assumed, with reaction
(1) as the rate-limiting step. Hence, the rate of formaldehyde pro-
duction (P) from methane can be written as:
P = K1 [OH] x [CH4] (8)
Using K1 = 2.4 x 10-12 e-1710/T (Lowe et al., 1981), OH pro-
files for latitude 45 °N (Logan, 1980), and a mean tropospheric methane
mixing ratio of 1.18 mg/m3, equation (5) can be numerically inte-
grated over a 10-km high troposphere to yield an average column formal-
dehyde production rate, due to methane oxidation, of 9 x 10-5 g/cm2
per year.
Similar results are obtained using a mean tropospheric OH concen-
tration of 6.5 x 105 molecules/cm3 (Volz et al., 1981) with a mean
methane mixing ratio of 1.18 mg/m3 giving a column formaldehyde pro-
duction in a 10-km high troposphere of 8 x 10-5g/cm2 per year. This
is equivalent to an average world production rate of formaldehyde from
methane of 4 x 1011 kg/year, which greatly exceeds the total indus-
trial formaldehyde production rate (6 x 109 kg/year).
Various processes contribute to the removal of formaldehyde from
tropospheric air. The action of solar ultraviolet radiation on formal-
dehyde results in its photolysis via two channels (Moortgat et al.,
1978; Calvert, 1980).
HCHO + h v -> H2 + CO (9)
-> H + HCO (10)
Formaldehyde is also removed from the troposphere by reaction with
the OH radical (Stief et al., 1980).
HCHO + OH -> HCO + H20 (11)
HCO + O2 -> HO2 + CO (12)
Through the reaction series (1)-(4) and reactions (9)-(12), CO and
H2 are produced in the atmosphere via formaldehyde as an intermediate
product. The destruction of one methane molecule leads to the pro-
duction of approximately one formaldehyde molecule and ultimately to
the production of a CO molecule. The series of reactions also results
in a net production of HO2 radicals, resulting in an overall increase
in the chemical reactivity of the atmosphere.
From equations (9), (10), and (11), it follows that the chemical
destruction of formaldehyde (D) is given by:
D = [HCHO][K11[OH] + J9 + J10] = [HCHO] (13)
tau
where K11 is the rate constant of equation (11), J9 and J10 are the
photodissociation coefficients for equations (9) and (10) and tau [s]-1
is the chemical life-time of formaldehyde in the lower troposphere.
Substituting J9+J10 = 4.5 x 10-5 s -1 (mean estimated from Calvert,
1980), K11 = 1.05 x 10-11 (Stief et al., 1979), and [OH] = 5 x 106
molecules/cm3 (Logan et al., 1981) into equation (13) yields an
average chemical life-time for formaldehyde in the lower troposphere
during daylight, of 3 h. Under atmospheric conditions in the presence
of nitrogen dioxide (NO2), the half-life of formaldehyde was found to
be 35 min (Bufalini et al., 1972).
At ground level in the atmosphere, reaction with the OH radical is
the dominant removal process for formaldehyde. However, in the first
few kilometres of the troposphere, the importance of the OH radical as
a removal process decreases with altitude and the photodissociation
coefficients J9 and J10 increase in importance.
Formaldehyde is also removed from the troposphere by rainout
(gaseous constituents of the atmosphere are absorbed during the forma-
tion of cloud droplets), washout (falling raindrops scavenge gases,
particles, and aerosols from the atmosphere), and by deposition at the
surface. However, these processes are only of minor importance in the
free troposphere. For example, from formaldehyde measurements made in
rainwater collected at an equatorial site in the Pacific, Zafiriou et
al. (1980) estimated that rainout was responsible for removing only 1%
of the formaldehyde produced in the atmosphere by the oxidation of
methane. In addition, Warneck et al. (1978) showed that washout, as a
removal process for gaseous formaldehyde in the troposphere, is import-
ant only in polluted regions and may be ignored in unpolluted air.
Dry deposition at the surface is usually defined by a deposition
velocity, (vo (cm/second)), and the flux (fo) to the surface may be
estimated by:
fo = vo x [HCHO]o (14)
where [HCHO]o is the mean formaldehyde concentration above the
surface.
The deposition velocity depends on the surface. For example, from
measurements made at an equatorial Pacific atoll, Zafiriou et al.
(1980), deduced a value for vo of 0.4 cm/second at the ocean surface.
The mean formaldehyde mixing ratio, [HCHO]o, measured during
an oceanographic expedition in the north and south Atlantic, was
0.29 x 10-3 mg/m3, corresponding to a concentration of 5.9 x 109 mol-
ecules/cm3 (Lowe et al., 1981). With a deposition velocity of
0.4 cm/second, equation (14) suggests a loss due to deposition at the
ocean surface of 2.4 x 109 molecules/cm2 per second or about 4% of
the column formaldehyde production from methane oxidation calculated
above. Although vo for formaldehyde is expected to vary with wind vel-
ocity, it is unlikely to exceed 1 cm/second. Hence, loss of formal-
dehyde from the troposphere due to deposition will only be important
near the surface itself.
More recently, consideration has been given to the possibility of
how much formaldehyde indirectly contributes to the overacidification
of precipitation (Richards et al., 1983). Formaldehyde reacts with
sulfur dioxide (SO2) and gives off relatively concentrated hydroxy-
methanesulfonic acid, whereby SO2 may contribute to the acid content
of precipitation without preceding oxidation to sulfuric acid, which is
a relatively slow process. More in-depth investigations have to be
carried out, in order to ascertain to what extent this process is
important for acid formation.
4.2 Transformation
4.2.1 Special products of degradation under specific conditions
Highly carcinogenic bis(chloromethyl)ether can be produced by a
condensation reaction between formaldehyde and hydrogen chloride
(Thiess et al., 1973; Nelson, 1977; Albert et al., 1982; Sellakumar et
al., 1985). The maximum equilibrium concentration of bis(chloro-
methyl)ether generated from atmospheric formaldehyde and hydrogen
chloride was estimated to reach 4 x 10-16 ppb; it was concluded that
this represented little impact on human health (NRC, 1981). According
to Keefer & Roller (1973), formaldehyde is able to catalyze nitro-
sation of a series of secondary amines to carcinogenic nitrosamines or
N -nitroso-compounds.
4.2.2 Microbial degradation
Formaldehyde released into the aquatic environment appears to
undergo relatively rapid biodegradation. Kamata (1966) examined the
biodegradation of formaldehyde in natural water obtained from a stag-
nant lake in Japan. Under aerobic conditions, known quantities of added
formaldehyde were decomposed in ca. 30 h at 20 °C, anaerobic decompo-
sition required ca. 48 h. No decomposition was noted in sterilized
water.
Various activated sludges and microorganisms isolated from acti-
vated sludges have been shown to be very efficient in degrading formal-
dehyde in aqueous effluents, providing the formaldehyde concentration
does not exceed 100 mg/litre (Verschueren, 1983). Essentially complete
degradation is achieved in 48-72 h, if the proper temperature and nu-
trient conditions are maintained (Kitchens et al., 1976). Grabinska-
Loniewska (1974) isolated 44 bacteria strains from an industrial acti-
vated sludge and found that formaldehyde was used as a sole carbon
source by various Pseudomonas strains but not by strains of
Achromobacter , Flavobacterium , Mycobacterium , or Xanthomonas . Several
studies have revealed significant degradation of formaldehyde by mixed
cultures obtained from sludges and settled sewage (Heukelekian & Rand,
1955; Hatfield, 1957; Sakagami & Yokoyama, 1980; Speece, 1983; Behrens
& Hannes, 1984), while in other studies, little or no degradation has
been found (Placak & Ruchhoft, 1947; Gerhold & Malaney, 1966; Belly &
Goodhue, 1976; Kalmykova & Rogovskaya, 1978; Chou et al., 1979).
A number of pure culture studies have shown that formaldehyde is
biologically degradable. Cell extracts of Pseudomonas methanica and
Methylosinus trichosporium (Patel et al., 1979) and cell-free extracts
of yeast strains of the Candida sp. are able to oxidize formaldehyde
(Fujii & Tonomura, 1972, 1974, 1975; Sahm, 1975; Pilat & Prokop, 1976).
Cell extracts of Pseudomonas oleovorans (Sokolov & Trotsenko, 1977),
Pseudomonas putida Cl (Hohnloser et al., 1980), Hansenula polymorpha
(Van Dijken et al., 1975), Methylococcus capsulatus (Patel & Hoare,
1971), Methanobacterium thermoautotrophicum , M. voltae and M.
jannaschii (Escalante-Semerena & Wolfe, 1984) and Alcaligenes faecalis
(Marion & Malaney, 1963) can also oxidize formaldehyde.
Yamamoto et al. (1978) isolated 65 strains of methanol-utilizing
bacteria from seawater, sand, mud, and weeds of marine origin and found
that all were able to use formaldehyde as a sole carbon source for
growth. In contrast, Kimura et al. (1977) found that 336 strains of
bacteria, isolated from coastal seawater and mud, could not use formal-
dehyde as a sole carbon source for growth.
5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE
5.1 Environmental Levels
5.1.1 Air
Measurements in maritime air yielded average formaldehyde concen-
trations of < 1-14 µg/m3 (Table 9).
Table 9. Measurements of aldehyde mixing ratios in the air
near the grounda
-----------------------------------------------------------------------------
Location RCHO HCHO Number Reference
of
measure-
(µg/m3) ments
-----------------------------------------------------------------------------
Baltic sea coast - 0.7-2.7 5 Hadamczik (1947)
Panama 1.2-4.8 - ? Lodge & Pate (1966)
Antarctica <0.6-12 - ? Breeding et al. (1973)
Panama <0.3-3.7 - ? Breeding et al. (1973)
Amazon Basin 1.2-7.4 - ? Breeding et al. (1973)
Irish west coast - 0.1-0.5 5 Platt et al. (1979)
Eastern Indian Ocean - < 1-14 63 Fushimi & Miyake (1980)
Central Pacific - 0.1-0.8 7 Zafiriou et al. (1980)
South Africa - 0.3-1.0 5 Neitzert & Seiler
(1981)
Irish west coast - 0.1-0.6 36 Lowe et al. (1981)
Bürserberg, Austria - 0.05-2.3 55 Seiler (1982)
-----------------------------------------------------------------------------
a Modified from: Lowe et al. (1981).
Higher values were generally obtained in the equatorial zone and
the Pacific (Fushimi & Miyake, 1980; Guderian, 1981; Seiler, 1982).
Measurements of the Nuclear Research Centre (Jülich, Federal Republic
of Germany), carried out with different measurement procedures in the
North and South Atlantic, yielded values of 0.1 µg/m3 and less (Lowe
et al., 1981). In the vicinity of the Pacific islands, values of up to
14 µg/m3 were reported (Fushimi & Miyake, 1980). However, it should
be borne in mind that considerable technical difficulties are involved
in measuring such low concentrations, with ensuing uncertainties.
The values measured in continental air are higher (0-16 µg/m3).
Measurements in Bürserberg, Austria, at 1250 m above sea level (Seiler,
1982), showed a mean value of 0.6 µg/m3 with a variation range of
0.05-2.3 µg/m3.
Measurements made by the Federal Environmental Agency at
Deuselbach, Hunsrück, Federal Republic of Germany, have proved to be
representative for the air in the rural areas of Central Europe
(Seiler, 1982). The mean value was about 1.5 µg/m3, ranging from
0.1 to 4.5 µg/m3 (Seiler, 1982). The lowest values were measured when
there was a rapid inflow of maritime air over extended periods. The
elevated values were probably due to man-made organic compounds that
had been transported long distances. Values of 6 µg/m3 generally ap-
pear together with increased concentrations of carbon monoxide and
sulfur dioxide, indicating man-made air pollution. Man-made emissions
dominate in the highly industrialized areas of Central Europe (Ehhalt,
1974).
Pronounced diurnal concentrations of formaldehyde are recognizable.
A typical example is given in Fig. 2. The resulting values are higher
in summer than in winter. They vary from season to season because of
the variation in intensity of the ultraviolet radiation.
5.1.1.1 Air in the vicinity of industrial sources and in urban communities
Estimated formaldehyde concentrations in emissions from various
sources are summarized in Table 10.
Table 10. Estimated formaldehyde concentrations in emissions
from various sourcesa
-------------------------------------------------------------
Emission source Formaldehyde level
-------------------------------------------------------------
Natural gas combustion
Home appliances and 2400-58 800 µg/m3
industrial equipment
Power plants 15 000 µg/m3
Industrial plants 30 000 µg/m3
Fuel-oil combustion 0-1.2 kg/barrel oil
Coal combustion
Bituminous < 0.005-1 g/kg coal
Anthracite 0.5 g/kg coal
Power plant, industrial and
commercial combustion
Incinerators
Municipal 0.3-0.4 g/kg refuse
Small domestic 0.03-64 g/kg refuse
Backyard 11.6 g/kg (max) refuse
Oil refineries
Catalytic cracking units 4.27 kg/barrel oil
Thermofor units 2.7 kg/barrel oil
Mobile sources
Automobiles 0.2-1.6 g/litre fuel
Diesel engines 0.6-1.3 g/litre fuel
Aircraft approximately 0.3-0.5 g/litre
fuel
-------------------------------------------------------------
a From: Kitchens et al. (1976).
Motor vehicle exhaust from automobiles not equipped with catalyzers
is the major source of formaldehyde in ambient outdoor air (Kitchens et
al., 1976).
Only a few highly industrialized areas, which are also areas with
heavy traffic, have been covered completely by measurements of the for-
maldehyde burden. In one such area in the Federal Republic of Germany
(Ludwigshafen-Frankenthal), annual mean values of 7-12 µg formalde-
hyde/m3 were measured during 1979-84. The annual mean value was the
arithmetic average of all half-hour values measured within a year
(long-term value). Peak concentrations in certain subareas, one square
km in size, ranged from 16 to 69 mg/m3. These were based on the 95-
percentile, i.e., 5% of the measured values were allowed to be in
excess of the prescribed parameters for concentrations in ambient air
(MSGU RP, 1984). The majority of subareas showed 95-percentile values
of about 25 µg/m3.
A mean value of 7 µg/m3 was determined in 1971-73 for the 43
measurement points in the Lower Main District, Federal Republic of
Germany, which is a radial measuring network with downtown
Frankfurt/Main (Federal Republic of Germany) as its centre. This was
based on 1-h measurements (n = 862). The 95% value of the cumulative
frequency distribution was 18 µg/m3, and the 4 highest single values
were 69, 65, 59, and 52 µg/m3 (Lahmann, 1977).
In another area at Mainz-Budenheim (Federal Republic of Germany),
continuous exposure to 8-20 µg/m3 was measured, with short-term
values of 23-99 µg/m3. Analysis of the causes of these high levels
showed that they were not only caused by industrial emissions. Individ-
ual measurements showed a correlation with carbon monoxide levels and
were not season-dependent. Hence, it can be assumed that motor vehicles
not equipped with catalyzers are responsible, to a considerable extent,
for the concentrations in ambient air (section 5.1.1.2). Usually, con-
centrations in ambient air are below 1 µg/m3. Data on concentrations
of formaldehyde in ambient air are presented in Table 11.
Formaldehyde concentrations in ambient air in areas with a high
level of air pollution, away from the vicinity of industrial plants,
are presented in Table 12.
Ambient air concentrations of formaldehyde, measured in Los
Angeles, California, during the autumn in 1961 and 1966, were
0.006-0.197 mg/m3 (Kitchens et al., 1976) and a daily average of
0.06-0.148 mg/m3 (Patterson et al., 1976), respectively. Concen-
trations of formaldehyde in the Los Angeles area ranged from 0.003 to
0.167 mg/m3 in 1969 (Kitchens et al., 1976). More recent air measure-
ments taken during 1979 in Los Angeles indicated levels of less than
18.5 µg formaldehyde/m3 (Versar Inc., 1980).
The results of continuous analyses of formaldehyde concentrations
in ambient air at the National Autoexhaust Monitoring Station at
Kasumigaseki in Tokyo were studied by Matsumura et al. (1979). The
hourly, daily, monthly, and yearly average concentrations were 1-88,
1-34, 3.7-23, and 5.5-12.6 µg/m3 (1-73, 1-28.4, 3.1-19.1, and 4.6-
10.5 ppb), respectively, with a 9-year average value of 8.5 µg/m3
(7.1 ppb). Daily average concentrations showed logarithmic normal
distribution. Ratios of the daily to hourly average concentrations
were about 1 to 2. The daily maximum value was observed at around noon
and the yearly maximum was found during June and August.
Richards et al. (1983) collected cloud water samples in the Los
Angeles Basin during 5 aircraft flights (altitude not reported) and
found a median of 2 mg formaldehyde/litre (68 µmol/litre) (range, 11-
142 µmol/litre).
Measurements taken in 4 cities in New Jersey showed median daily
concentrations in the range of 4.67-8.12 µg/m3 (Cleveland et al.,
1977).
A study in Switzerland showed formaldehyde concentrations of
11.4-12.3 µg/m3 in street air (Wanner et al., 1977). Maritime air in
the northern part of the Federal Republic of Germany has been reported
to contain formaldehyde at levels of 0.12-8 µg/m3 (Platt et al.,
1979).
Tanner & Meng (1984) observed strong seasonal variations in the
levels of formaldehyde, maximum levels being observed in the summer.
The formaldehyde samples were collected at an unidentified northeast
coastal site in the USA, using an impinger containing acetonitrile and
DNPH; they were analysed using high-pressure liquid chromatography.
The concentrations ranged from 1 to 58 µg/m3 (0.9 to 48 ppbv) with an
overall mean of 9 µg/m3 (7.5 ppbv). The monthly average ambient
levels were:
equivalent to:
July/August: 1982: 15.8 ppbv, 16 samples 16 µg/m3
October/November:1982: 4.4 ppbv, 24 samples 4 µg/m3
March: 1983: 3.8 ppbv, 59 samples 4 µg/m3
April: 1983: 11.2 ppbv, 11 samples; and 11 µg/m3
May: 1983: 12.2 ppbv, 25 samples 12 µg/m3
Table 11. Levels of formaldehyde in ambient aira
---------------------------------------------------------------------------------------------------------
Country Sampling area % of Analytical Source HCHOb Comment Reference
samples method (µg/m3)
---------------------------------------------------------------------------------------------------------
Federal Eifel Region - 2,4 dinitrophe- easterly 5.0- Within boundary Schmidt &
Republic (51°N, 6°E) nylhydrazine winds 6.1 layer Lowe
of from indus- 0.37 above boundary (1981)
Germany trial area; layer
westerly 0.12 5-7 km altitude
maritime
winds
Federal Mainz-outskirts 8 glass fibre automobiles 0.063 formaldehyde Klippel &
Republic of city; 54 filters some auto- 0.037- aerosol only Warneck
of Deuselbach-rural mobile 0.39 (1978)
Germany industry
France Paris roadside 2,4-dinitrophe- automobiles 41- total aldehydes Favart et
nylhydrazine 120 al. (1984)
Ireland Mace Head and 28 glass fibre maritime air 0.049- formaldehyde Klippel &
Loop Head filters 0.082 aerosol only Warneck
located on (1978)
shoreline
Italy Northern - near 15 2,4-dinitrophe- 7.06 De Bortoli
Swiss border nylhydrazine et al.
(1985)
Nether- Terschelling 350 chromatropic acid 7.4 Guicherit &
lands Island - small at each method Schulting
population; site (1985)
Delft - small
city; Rotterdam -
heavily industrialized
---------------------------------------------------------------------------------------------------------
Table 11 (contd).
---------------------------------------------------------------------------------------------------------
Country Sampling area % of Analytical Source HCHOb Comment Reference
samples method (µg/m3)
---------------------------------------------------------------------------------------------------------
USA Rural Illinois 30 3-methyl-2- - <1.2- total Breeding
and Missouri; benzothiazolone 5.0 aldehydes et al.
3 samples hydrazone (1973)
1 m above ground,
1 sample 20-15 m
above tree tops
USA Los Angeles- 31 30 or 60 litres - 49.1 July-November, Altshuller
downtown of air at 1 litre 55.3 1960 & McPherson,
per min through Sept-Nov. 1961 (1963)
20 ml of 0.1%
chromotropic acid
in conc. H2SO4
USA Riverside, 32 Fournier-transform < 5- Tuazon et
California infrared system 12 al. (1978)
USA Lennox, Calif., 36 Microimpinger industrial 0.6- levels between Grosjean &
roof top method with emissions 48.6 07h30 and 20h00 Swanson,
Azusa, Calif., 36 2,4-dinitro- photo- 0.9- during air pol- (1983)
roof top phenylhydra- chemical 43 lution episode
zine pollutants
Los Angeles 20 4.5- between 9h30 and
Area 70.1 16h20 during air
pollution episode
USA Bayonne, hourly dichlorosulfit- automobiles 17.2- range of max. Cleveland
Camden, samples omercurate 20.0 levels from 4 et al.
Elizabeth between complex and acid sites (1977)
and Newark, May 1 and bleached pararo- 4.7- range of average
New Jersey Sept. 30, saniline hydro- 8.1 levels from
1974 chloride 4 sites
---------------------------------------------------------------------------------------------------------
a Modified from: Meek et al. (1985).
b Unless other specified, mean or ranges.
Table 12. Measurements of formaldehyde in ambient air in areas remote
from industrial emission sourcesa
--------------------------------------------------------------------------------------------------------
Location Period Mean value Maximum Remarks Reference
or range value
(ug/m3) (ug/m3)
--------------------------------------------------------------------------------------------------------
Federal Republic of Germany
Berlin 1973-74 0.6 18 118-h mean Lahmann &
2.1 32 119-h mean Prescher
Berlin - Airport 2.2 29 72-h mean (1979)
Berlin - Steglitz 1966-67 39 243-h mean Lahmann & Prescher
Berlin - Tempelhof 1973-74 0.5 12 71-h mean (1979)
Frankfurt - Airport 1983 9-11 23 half-hour mean BGA (1985)
Frankfurt - City 1983 7-13 9-25 BGA (1985)
Köln - Neumarkt December 1975 2.3 8.5 95-percentile Deimel (1978)
June 1978 8.2 18.3 95-percentile Deimel (1978)
June 1978 23.1 rush-hour traffic Deimel (1978)
Mainz - University 1979 4.4 7.5 65 measurements Seiler (1982)
Mainz - Finthen 1979-80 1.6 3.8 33 measurements Seiler (1982)
Switzerland
Street air 1976 11.4-12.3 - Wanner et al. (1977)
USA
California 1960-80 8-70 160 Versar Inc.(1986)
Los Angeles, California 1961-66 6-197 - Kitchens et al.
(1976)
Northeastern coastal site 1982-83 1-48 - Tanner & Meng
(1984)
--------------------------------------------------------------------------------------------------------
a From: BGA (1985).
5.1.1.2 Emissions from industrial plants
(a) Chemical industry
The following emission factors per metric tonne of formaldehyde
produced by formaldehyde-manufacturing plants in the Federal Republic
of Germany are given on a 100% basis (section 3.2.1.1).
Silver catalyst process with afterburning of flue gas in power
plant and gas displacement devices: 0.003-0.008 kg/metric tonne formal-
dehyde produced; silver catalyst process with flaring of off-gas,
without gas displacement devices: 0.05-0.2 kg/metric tonne produced;
metal-oxide catalyst process without afterburning: approximately
0.5 kg/metric tonne produced; metal-oxide catalyst process with after-
burning but without gas displacement devices: 0.08-0.2 kg/metric tonne
produced.
(b) Wood-processing industry
Several studies are available that deal with formaldehyde emissions
at particle board factories in the Federal Republic of Germany (WKI,
1978; Marutzky et al., 1980; Schaaf, 1982).
In 1980, the emissions in the exhaust air of several plants reached
a mean value of 40 mg formaldehyde/m3 off-gases. No measures had been
taken at any of the plants to clean the off-gases. Pilot studies at a
particle board factory showed that a concentration (pure gas) of less
than 20 mg/m3 could be obtained using bioabsorption equipment. Mean-
while, the emittable formaldehyde content of the resins used was
further reduced, resulting in even lower formaldehyde concentrations in
the off-gases (BGA, 1985).
5.1.1.3 Emissions from furnaces
Incomplete combustion in furnaces is also a cause of formaldehyde
emission (Schmidt & Götz, 1977). Various types of furnaces differ
considerably in their emission of formaldehyde, depending on the rate
of combustion.
Investigations on a small solid-fuel boiler running on wood
(Schriever et al., 1983) showed that there was a formaldehyde concen-
tration of more than 1000 mg/m3 in the gaseous emission during the
first phase of combustion, i.e., that of degasification. During the
subsequent burning-out phase, the emissions of formaldehyde were about
50-100 mg/m3.
Lipari et al. (1984) measured formaldehyde emissions in the exhaust
gases of a free-standing wood-burning fireplace in the laboratory.
When burning green ash (quartered logs), values of 708 mg/kg wood were
found; the formaldehyde content of the exhaust gases, when burning red
oak, ranged from 89 mg/kg (quartered logs) to 326 mg/kg (split wood).
It is likely that wood burning in the home is a major source of primary
aldehydes during the winter.
In the Federal Republic of Germany, it is estimated that about 2.8
million tonnes of firewood off-gas are consumed in small heating
systems for heating buildings. On the basis of an average formaldehyde
concentration of 100 mg/m3 firewood, an overall annual emission of
approximately 1000 tonnes of formaldehyde has been calculated.
5.1.1.4 Emissions from motor vehicles
Formaldehyde is also emitted as a product of incomplete combustion
by internal combustion engines. The amounts emitted depend greatly on
the operating conditions. Very high values are reached in emissions
from a cold engine. Kitchens et al. (1976) reported a formaldehyde
emission of 700 mg/litre gasoline or diesel fuel. Given an assumed
average value for gasoline consumption of 23 million tonnes and for
diesel fuel consumption of 13 million tonnes in the Federal Republic of
Germany, the total formaldehyde emission would be 35 000 tonnes per
year. Hence, motor vehicles are by far the most important source of
formaldehyde emission. The use of exhaust catalytic converters reduces
the emissions to less than one-tenth. Emission factors of between 1.8
and 2.4 mg/km have been reported for the USA (VDA, 1983).
Four-stroke engines, running on alcohol, emit more aldehydes than
similar engines fuelled with petrol. The formaldehyde concentration in
the exhaust fumes can be reduced by a factor of 10 by installing
exhaust catalytic converters in vehicles powered with methanol, but the
concentration is still higher than that of vehicles with petrol-burning
engines. Emission factors of about 250-300 mg/km have been given for
vehicles with methanol-burning engines without an exhaust catalyser
(Menrad & König, 1982). The odour of such amounts of formaldehyde is
perceptible near the vehicle. Diesel engines also emit formaldehyde;
diesel oil produces 1-2 g aldehydes/litre of which 50-70% is
formaldehyde (Guicherit & Schulting, 1985).
5.1.2 Water
In the atmosphere, formaldehyde is absorbed during the formation of
cloud droplets ("rainout") or scavenged by falling raindrops
("washout"). Some concentrations in rainwater and aerosols are
given in Table 13. When the rainfall continued for a long period,
remaining concentrations in the air of 0.05 µg/m3 (detection limit:
0.03 µg/m3) were found by Seiler (1982). Concentrations in
rainwater at a remote site in the central equatorial Pacific averaged
8 ± 2 µg/kg (Zafiriou et al., 1980). Kitchens et al. (1976) reported
concentrations of 0.31-1.38 mg/litre.
Table 13. Formaldehyde concentrations in rainwater and
aerosola
-------------------------------------------------------
Location (year) Rainwater Aerosol
concentration concentration
(mg/litre) (ng/m3)
-------------------------------------------------------
Mainz, Federal Republic 0.174 ± 0.085 -
of Germany (1974-77)
Deuselbach, Federal 0.141 ± 0.048 40.9 ± 26.0
Republic of (1974-76)
Ireland (1975, 1977) 0.142 ± 0.059 5.36 ± 2.4
Irelandb (1977) 0.111 ± 0.059 -
-------------------------------------------------------
a From: Klippel & Warneck (1978).
b Very clean air.
Fish-culture activities are also a source of formaldehyde in the
aquatic environment. Formalin is one of the most widely and frequently
used chemicals for treating fish with fungal or ectoparasitic infec-
tions. After use, formaldehyde solutions are often discharged into the
hatchery effluent (NRC, 1981).
5.1.3 Soil
Formaldehyde is formed in the early stages of plant residue
decomposition in soil (Berestetskii et al., 1981). It is degraded by
certain bacteria in the soil, and therefore bioaccumulation does not
occur. Completely polymerized urea-formaldehyde resins persist in the
environment and do not emit formaldehyde. Partially polymerized conden-
sation products of low relative molecular mass degrade gradually, thus
releasing formaldehyde vapour that can be broken down by soil micro-
flora (Kitchens et al., 1976; Hsiao & Villaume, 1978).
5.1.4 Food
There is some natural formaldehyde in raw food. Formaldehyde
concentrations in various food are given in Table 14.
Table 14. Formaldehyde content of foodstuffs
-----------------------------------------------------------------------------
Food Formaldehyde content Reference
(mg/kg)
-----------------------------------------------------------------------------
Fruits and vegetables
pear 60a (38.7)b Möhler & Denbsky (1970)
apple 17.3 (22.3) Tsuchiya et al. (1975)
cabbage 4.7 (5.3) Tsuchiya et al. (1975)
carrot 6.7 (10) Tsuchiya et al. (1975)
green onion 13.3 (26.3) Tsuchiya et al. (1975)
spinach 3.3 (7.3) Tsuchiya et al. (1975)
tomato 5.7 (7.3) Tsuchiya et al. (1975)
white radish 3.7 (4.4) Tsuchiya et al. (1975)
Meat
pig 20 Florence & Milner (1981)
sheep 8 Mills et al. (1972)
poultry 5.7 Möhler & Denbsky (1970)
Milk and milk products
goat's milk 1 Mills et al. (1972)
cow's milk up to 3.3 Möhler & Denbsky (1970)
cheese up to 3.3 Möhler & Denbsky (1970)
Fish
freshwater (fumigated) 8.8 Möhler & Denbsky (1970)
sea (fumigated) 20 Möhler & Denbsky (1970)
cod (frozen) 20 Rehbein (1986)
shrimp (live) 1 Radford & Dalsis (1982)
crustacea 1-60 Cantoni et al. (1977)
(Mediterannean)
crustacea (ocean) 3-98 Cantoni et al. (1977)
-----------------------------------------------------------------------------
a Analysis by chromotropic acid.
b Analysis using Schiff's reagent.
Accidental contamination can occur through fumigation (e.g., in
grain) or by using formaldehyde-containing food additives.
Hexamethylenetetramine has been reported to decompose gradually to
formaldehyde under acidic conditions or in the presence of proteins
(Hutschenreuter, 1956; WHO, 1974a). Its use is not recommended when
there is a possibility that nitrate might also be present in food,
because of the risk of nitrosamine formation (WHO, 1974b).
Formaldehyde can be introduced into food through cooking and
especially through smoking of food, from utensils, and as a combustion
product; it can be eluted from formaldehyde-resin plastic dishes with
water, acetic acid, and ethanol in amounts directly proportional to the
temperature (Table 15, 16).
Release of formaldehyde may increase with the repeated use of
melamine resin tableware (Table 16). The molar concentration ratio of
formaldehyde to melamine (y), in 4% acetic acid maintained at 95 °C for
30 min in melamine cups, decreases biexponentially between the first
and fifth treatments according to the following formula: 1n y = -1.0755
ln x + 2.2462, where x = the number of times that the heat treatment is
repeated. After the sixth treatment, the value of y is reported to
remain constant (Inoue et al., 1987).
Daily intake of formaldehyde through food is difficult to evaluate,
but a rough estimate from available data is in the range of 1.5-14
mg/day for an average adult, most of it in a bound and unavailable
form.
5.2 Indoor Air Levels
Indoor air levels of formaldehyde in various countries were
presented during the International Conference on Indoor Air Quality in
Stockholm (Berglund et al., 1984).
A survey of indoor air quality under warm weather conditions, in a
variety of residences in Houston, Texas, USA, not selected in response
to occupant complaints, revealed a distribution of indoor formaldehyde
concentrations ranging from < 0.01 to 0.35 mg/m3, with an arithmetic
mean of 0.08 mg/m3 (Stock & Mendez, 1985). Levels in approximately
15% of the monitored residences exceeded 0.12 mg/m3. Formaldehyde
levels depended on the age and structural type of the dwelling. These
factors were not independent and reflected the influence of more funda-
mental variables, i.e., the rate of exchange of indoor and outdoor air
and the overall emission potential of indoor materials. The results of
this survey suggested that considerable population exposure to excess
(>0.12 mg/m3) formaldehyde concentrations might have occurred in the
residential environment, indicating the need for improved control
strategies.
Hawthorne et al. (1984) measured formaldehyde levels in 40 East-
Tennessee homes. Levels in older houses averaged 0.048 mg/m3 while
those in houses less than 5 years old averaged 0.096 mg/m3.
The effects of foliage plants on the removal of formaldehyde from
indoor air in energy-efficient homes is discussed in section 7.3.
Measurements made in living areas, schools, hospitals, and other
buildings are listed in Table 17 to 19.
Table 15. Migration of formaldehyde from melamine and urea-resin tableware (mg/litre) into
different solvents. Detection limit 0.4 mg/litrea.
--------------------------------------------------------------------------------------------
Resin Temperature Water 4% Acetic acid 15% Ethanol 35% Ethanol
30 minb 30 minc 30 minb 30 minc 30 minb 30 minc 30 minb 30 minc
--------------------------------------------------------------------------------------------
25 °C n.d.d n.d. n.d. n.d. n.d. n.d. n.d. n.d.
60 °C n.d. n.d. 0.5 n.d. 0.4 n.d. n.d. n.d.
Melamine 70 °C n.d. n.d.
resin 80 °C 0.5 1.4 0.6 3.0 0.5 1.6 0.5 1.4
90 °C 2.2 2.6
100 °C 2.6 5.2 0.8 8.9 0.5 4.6 0.5 4.8
--------------------------------------------------------------------------------------------
25 °C 0.4 0.4 0.4 0.5 0.5 0.5 0.4 0.5
60 °C 2.9 4.3 3.1 8.3 3.1 3.8 2.9 4.1
Urea 70 °C 5.0 13.0
resin 80 °C 9.1 23.4 9.6 126.0 7.4 30.0 8.6 28.2
90 °C 13.0 39.2
100 °C 18.0 48.2 27.6 648.0 19.0 54.0 18.5 50.4
--------------------------------------------------------------------------------------------
a From: Homma (1980).
b Standing at room temperature.
c Maintained at a definite temperature.
d Not detected.
Table 16. Migration from melamine cups with 4% acetic acid
concentration in the migration solutiona
-------------------------------------------------------------------
Conditions Melamine Formaldehyde
mg/litre mg/litre
-------------------------------------------------------------------
60 °C, 30 min 0.5 ± 0.6 ndb
Microwave oven 1.5 min (90 °C)
and stood at room temperature for
30 min (60 °C) 1.7 ± 1.2 (1.1 ± 0.4)
95 °C, 30 min
repetition 1 9.5 ± 3.1 (4.1 ± 0.8)
2 28.1 ± 6.0 (12.0 ± 2.6)
3 37.7 ± 10.3 (17.3 ± 3.4)
5 46.4 ± 13.9 (19.4 ± 2.8)
7 50.4 ± 3.6 (22.2 ± 2.2)
-------------------------------------------------------------------
a From: Ishiwata et al. (1986).
b Not detected.
Tobacco smoke contains an average of 48 mg formaldehyde/m3 and is
an important source of formaldehyde in indoor air. Two cigarettes
smoked in a 30 m3 room increased the formaldehyde level to more than
0.1 mg/m3 (Jermini et al., 1976). Formaldehyde from tobacco smoke is
absorbed by furniture, carpets, and curtains, and only slowly desorbed
if the formaldehyde concentration in the indoor air decreases. Par-
ticle boards and, to a lesser extent, urea-formaldehyde-foam insulation
(UFFI) were also listed as causes of increased indoor exposure. Disin-
fectant products may cause high exposure. These sources of emission
are described in Table 17, 18, and 19.
Formaldehyde concentrations in 49 Dutch houses and 3 old peoples'
homes where no UF-foam or particle board had been used were analysed by
Cornet (1982). The houses were of different construction types and
periods, in which it could be established that no particle board as
construction material nor UF-foam had been used. However, several of
these houses had particle board furniture. Overall, construction types
and conditions of use were typical for Dutch circumstances. Average
formaldehyde concentrations were 65 µg/m3, ranging mainly from 30 to
100 µg/m3. Ventilation rates ranged usually from 0.3-1.5 air changes per
hour in living rooms and 0.2-1.2 in bedrooms. During the measurements
no smoking took place.
No clear correlations could be established between the amount of
particle board present in furnishings, ventilation rates, and formal-
dehyde concentrations.
5.2.1 Indoor exposure from particle boards
Nuisance from bad smells led to complaints by students and teachers
in several new schools in Köln, Federal Republic of Germany, in 1975
and 1976. Formaldehyde concentrations of up to 1.2 mg/m3 were measured
with the windows closed (Deimel, 1978). A combination of ceilings and
furniture made of particle boards and insufficient ventilation was the
cause of these high indoor concentrations (Anderson et al., 1975).
There have been complaints from schools, kindergartens, private homes,
and, especially in the USA, mobile homes. Formaldehyde concentrations
of more than 0.12 mg/m3 and sometimes more than 1.2 mg/m3 were
measured.
During the 1970s, increased use of UF-bonded particle board
as a construction material in The Netherlands resulted in many
consumer complaints, attributed to formaldehyde. In 1978, a level of
120 µg/m3 was officially recommended as an acceptable upper limit.
In the years 1978-81, measurements of indoor formaldehyde concen-
trations were carried out, guided by consumer complaints. In 1981, a
summary of 950 measurements was presented to the Dutch Parliament
(Dutch State Secretary of Health and Environment, 1981). In 435 cases,
formaldehyde concentrations exceeded 120 µg/m3, whereas in 515
cases, notwithstanding complaints, levels were below 120 µg/m3.
Since 1981, many hundreds of measurements of formaldehyde levels in
houses, schools, hospitals etc. have been carried out, guided also by
consumer complaints. But the overall picture has remained the same,
except for extremes; values exceeding 200-250 µg/m3 have seldom been
reported since the introduction of the new standard. However, occasion-
ally, higher concentrations of up to 400 µg/m3 have arisen as a
result of the use of particle board or trimmings of bad quality in
furniture.
Table 17. Formaldehyde levels in homesa
---------------------------------------------------------------------------------------------------------
Country No. Average Room Air Humidity HCHO Comments Reference
(Year) of age of volume temp. (% relative (mg/m3)b
homes homes (m3) (°C) humidity or
gH2O/kg air)
---------------------------------------------------------------------------------------------------------
Canada 378 - - 0.042 homes without UFFI
(1981) (2.6% > 0.123) UFFI (1981)
1897 - - 0.066 homes with UFFI UFFI
(10.4% > 1.23) (1981)
Canada 6 67 21.5 61% 0.014 homes without Georghiou
(1981) (8-100) (21-23) (59-65) (<0.012-0.027) UFFI & Snow
years (1982)
43 52 20.4 62% 0.066 homes with UFFI Georghiou
(3-140) (15-25) (54-71) (<0.012-0.246) & Snow
years (1982)
Canada 46 - - - 23-48% 0.11 low leakage Dumont
(1983) (0.04-0.30) homes (1984)
39% > 0.123
Denmark 25c 15.3 23d 22.8 7.1 0.62 Andersen
(1973) months et al.
(1975)
25g 15.3 23d 23 7 0.64 corrected for Andersen
months standard et al.
conditionse (1979)
Denmark 7f - - 26 9.7 0.64
(1976) 7g - - 23 7 0.30 corrected for Andersen
standard con- et al.
ditions (1979)
Finland 432 - - - 0.20 average Niemalä
0.11 25th percentile (1985)
0.33 75th percentile
---------------------------------------------------------------------------------------------------------
Table 17 (contd).
---------------------------------------------------------------------------------------------------------
Country No. Average Room Air Humidity HCHO Comments Reference
(Year) of age of volume temp. (% relative (mg/m3)b
homes homes (m3) (°C) humidity or
gH2O/kg air)
---------------------------------------------------------------------------------------------------------
Germany, 1 0.069 middle of living Schulze
Federal and bedroom (1975)
Republic of
(1974) 1 0.10 room near cup- Schulze
boards (1975)
1 furniture 60 0.039 middle of sick- Schulze
1-1.5 room near (1975)
years old cupboards
1 60 0.050 near cupboards Schulze
(1975)
1 new house 11 0.16 kitchen, fitted Schulze
cupboards (1975)
1 new house 54 0.10 living room Schulze
(1975)
1 new house 0.084 kitchen Schulze
(1975)
1 new house 0.075 living room Schulze
(1975)
1 old 35 0.242 living room Schulze
house (7 m3 of (1975)
cupboard space)
Germany, 984 57.3% < 0.05 Prescher
Federal 22.3% < 0.05 & Jander
Republic of 22.3% 0.05-0.07 (1987)
11.4% 0.071-0.096
3% 0.097-0.12
6% > 0.12
Italy 15 0.029 apartments and De Bortoli
(1983-84) (0.008-0.052) housing et al.
(1985)
---------------------------------------------------------------------------------------------------------
Table 17 (contd).
-----------------------------------------------------------------------------------------------------------
Japan up to
0.041 living room Matsumura
0.113 pre-fabricated et al.
house (1983)
Switzerland 8 < 6 months 0.33 just after Wanner &
(1981-82) to 1 year 0.14 occupancy Kuhn (1984)
The Nether- 15 0.27 before Dept. Nat.
lands corrective Housing &
(1980) measures taken Phys.
Planning
(1981)
8 0.29 before treatment
0.10 6 weeks after
treatment
The Nether- 5 21 56% 0.17 living rooms, Van der
lands before wal
(1977-1980b) treatment (1982)
21 60% 0.09 after treatment
5 20 54% 0.32 bedrooms before
treatment
21 60% 0.20 after treatment
36 0.34 average of highest
measurements
USA (1982) 40 0-30 years 0.076 ± 0.095 5903 Hawthorne
18 0-5 years 0.103 ± 0.112 measurements et al.
11 5-15 years 0.052 ± 0.052 (1983)
11 >15 years 0.039 ± 0.052
18 0-5 years 0.107 ± 0.114 spring
0.136 ± 0.125 summer
0.058 ± 0.068 autumn
---------------------------------------------------------------------------------------------------------
Table 17 (contd).
---------------------------------------------------------------------------------------------------------
Country No. Average Room Air Humidity HCHO Comments Reference
(Year) of age of volume temp. (% relative (mg/m3)b
homes homes (m3) (°C) humidity or
gH2O/kg air)
---------------------------------------------------------------------------------------------------------
USA (1982) contd.
11 5-15 years 0.053 ± 0.049 spring Hawthorne
0.060 ± 0.059 summer et al.
0.042 ± 0.043 autumn (1983)
11 >15 years 0.044 ± 0.063 spring
0.036 ± 0.046 summer
0.032 ± 0.028 autumn
USA (1981) 41 0.04 homes without Ulsamer
(0.012-0.098) UFFI et al.
(1982)
636 0.15 homes with UFFI
(0.012-4.2)
USA 244 UFFI homes Breysse
>1.23 2.8% of samples (1984)
0.61-1.22 1.9% of samples
0.12-0.60 24.1% of samples
<0.12 71.2% of samples
non-UFFI homes and
apartments
59 >1.23 1.8% of samples
0.61-1.22 1.8% of samples
0.12-0.60 36.3% of samples
<0.12 60.1% of samples
USA 13 building 0.12 (median) Dally
(1978-79) material et al.
3-92 months (1981)
(5.2 months
median)
---------------------------------------------------------------------------------------------------------
Table 17 (contd).
---------------------------------------------------------------------------------------------------------
USA (1979) 1 0.098 energy Berk et
(0.04-0.15) efficient al. (1980)
house (0.01 mg
HCHO/m3 outdoors)
1 0.081 unoccupied without
±0.007 furniture
0.225 unoccupied with
±0.016 furniture
0.263 ± 0.026 occupiedh,
daytime
0.141 ± 0.044 occupiedh,
nighttime
USA 9 2 years 445 0.044 ± 0.022 airtight Offermann
(1980/81) (total) construction et al.
(half had (1982)
gas appliances)
0.033 ± 0.020 mechanical venti-
lation
1 6 years 441 0.017 "loose" construc-
(total) tion
USA (1983) 20 <6 0.076 energy- Grimsrud
years efficient et al.
new homes (1983)
16 0.037 low ventilation
modernized homes
---------------------------------------------------------------------------------------------------------
a Modified from: Meek et al. (1985). Where blanks appear, relevant information not provided by authors.
b Means, ranges or standard deviations, unless otherwise specified.
c Ventilation = 0.8 air changes/h.
d Loading (ratio of unit area of formaldehyde source to room volume) = 1.2 m2/m3.
e Standard conditions were: 23 °C, 7 g H2O/kg air, 1 air change/h.
f Ventilation = 0.32 air change/h.
g Ventilation = 1 air change/h.
h House had a gas stove and 3 occupants, no cigarette smokers.
Table 18. Formaldehyde levels in mobile homesa
--------------------------------------------------------------------------------------------------------
Country No. of mobile Age of HCHO Comments Reference
homes studied homes (mg/m3)
--------------------------------------------------------------------------------------------------------
Germany, 1 year 5.26 trailer Schulze (1975)
Federal 1 year 1.06 trailer
Republic of opened up for 1 h
3 years 0.06 trailer shut for 1 day
3 1 year 0.11 trailer
3 2 years 0.05 trailer
USA 110 < 2 years 0.95 complaint homes, Washington Stone et al.
38 < 2 years 0.89 complaint homes, Wisconsin (1981)
66 < 2 years 1.04 complaint homes, Minnesota
< 2 years 0.66 random sample, Wisconsin
77 2-10 years 0.58 complaint homes, Washington
9 2-7 years 0.56 complaint homes, Wisconsin
43 2-10 years 0.34 complaint homes, Minnesota
USA 65 0.2-12 years 0.59 complaint homes, Wisconsin Dally et al.
median 1.3 (median) (1981)
years
USA 430 > 1.23 4 % of sample Breysse (1984)
0.61-1.22 18% of sample
0.12-0.60 64% of sample
< 0.12 14% of sample
USA 431 0.47 Ulsamer et al.
(0.012-3.60) (1982)
USA 65 0.20 65 out of 208; random Hanrahan et al.
(median) sample of mobile homes (1984)
in Wisconsin
--------------------------------------------------------------------------------------------------------
a From: Meek et al. (1985).
Table 19. Formaldehyde levels in public buildingsa
--------------------------------------------------------------------------------------------------------
Country No. of Average Loading, Air Ventila- HCHO Comments Reference
build- age of (m2/m3)b temp. tion (air (mg/m3)c
ings- buildings (°C) changes/h)
--------------------------------------------------------------------------------------------------------
Denmark 7 6 months - - 0.5 0.45 mobile day care Olsen (1982)
centre
Germany, 3 - - - - 0.469 schools containing Burdach &
Federal some UF building Wechselberg
Republic of material (1980)
441 dwellings, offices, Prescher
hospitals, joiner's (1984)
workshops, complaints
- - - - - 0.014-0.31 dwellings with
mean 0.06 gas cooking
- - - - - 0.064-0.2 dwellings without
mean 0.06 gas cooking
- - - - - 0.01-0.13 offices, smokers
mean 0.05
- - - - - 0.02-0.1 offices, non-smokers
mean 0.05
- - - - - 0.026-0.22 joiner's workshops
mean 0.12
- - - - - 0.012-0.1 hospital rooms
mean 0.05
--------------------------------------------------------------------------------------------------------
Table 19 (contd).
--------------------------------------------------------------------------------------------------------
Country No. of Average Loading, Air Ventila- HCHO Comments Reference
build- age of (m2/m3)b temp. tion (air (mg/m3)c
ings- buildings (°C) changes/h)
--------------------------------------------------------------------------------------------------------
Japan - - - - - 0.048 department store Matsumura
up to et al. (1983)
0.046 grocer's shop
0.035 offices
0.003 cinema
Switzerland 11 < 6 months - - - 0.410 office: measure- Wanner & Kuhn
ment taken after (1984)
recent occupancy
1 year - - - 0.160 and after ageing,
16 < 6 months 0.60 school: measurement
1 year taken after recent
occupancy and
0.23 after ageing
The Nether- 10 - - - - 0.758 average of highest Van Der Waal
lands measurements in (1982)
schools
13 - - - - 0.245 average of highest
measurements in
commercial esta-
blishments
1 - - - - 2.30 highest value in
UFFI building
Yugoslavia 24 - - 26 - 1.083 offices Kuljak (1983)
2 - - 30 - 2.60 stores
3 - - 18 - 0.15 furniture stores
--------------------------------------------------------------------------------------------------------
Table 19 (contd).
--------------------------------------------------------------------------------------------------------
Yugoslavia 6 1-3 years - - - 0.143 offices Kalinic
6 11-43 years 0.087 offices et al. (1985)
7 1-10 years 0.141 kindergarten
3 11-50 years 0.109 kindergarten
8 4-23 years 0.043 schools
2 90-100 years 0.023 schools
USA 1 4 years - - - 0.025-0.037 office recently Konopinski
renovated with (1983)
UF material
2 4 years - - - 0.36-1.22 office recently
renovated with
particle board
1 - - - - 0.14-0.45 particle board
shelving
1 - - - - 0.11-0.14 particle board
furniture and
plywood floors
--------------------------------------------------------------------------------------------------------
a Modified from: Meek et al. (1985). Where blanks appear, relevant information not provided by authors.
b Ratio of unit area of formaldehyde source to room volume.
c Means or ranges, unless otherwise specified.
5.2.2 Indoor air pollution from urea-formaldehyde foam insulation
(UFFI)
Foam made from specific aminoplastic resins is used for the thermal
insulation of spaces in walls or other elements of construction. In
this process, an acidic surfactant solution is foamed by compressed air
and continuously mixed with aqueous UF resin. Formaldehyde is emitted
during and after completion of the hardening process. The resulting in-
door exposure depends, among other factors, on the age of the building,
type of resin, the application and the care taken, the amount of excess
formaldehyde, the amount and rate of emission, the prevailing tempera-
ture, humidity, and rates of ventilation.
Most of the studies performed on UFFI and mobile homes have been
carried out in Canada and the USA (Table 18), but they are currently of
less importance.
Studies by Everett (1983) showed that there is some increase in
formaldehyde levels in dwellings, directly after foaming, but that this
decays over a period of a few weeks. Everett (1983) noted that, though
there were isolated high values up to 1.2 mg/m3, 70% of the results
after foaming were below 0.1 mg/m3.
Girman et al. (1983), conducting the 40-home East Tennessee study,
obtained formaldehyde measurements that led to the following major
conclusions:
The average formaldehyde levels exceeded 0.12 mg/m3 (0.1 ppm) in
25% of the homes;
Formaldehyde levels were positively related to temperature levels
in homes. In houses with UFFI, a temperature-dependent relationship
with measured formaldehyde levels frequently existed;
Formaldehyde levels generally decreased with increasing age of the
house. This is consistent with decreased emission from materials due to
aging;
Formaldehyde levels were found to fluctuate significantly both
during the day and seasonally.
5.2.3 Indoor air pollution from phenol-formaldehyde plastics
Popivanova & Beraha (1984) carried out a study on phenol-
formaldehyde penoplast in order to establish the amount and dynamics of
formaldehyde migration into the indoor air in relation to three major
factors, i.e., age of the material, air temperature, and air exchange
rate. Age of the material was found to be the most important factor
influencing formaldehyde migration, followed by temperature elevation.
The rate of air exchange was inversely related to formaldehyde
migration level. A mathematical model of these processes has been
developed and a regression equation proposed. A review of factors
influencing formaldehyde migration from formaldehyde resins was
published by Popivanova (1985).
5.2.4 Exposure to indoor air containing cigarette smoke
As with all other incomplete combustion processes, formaldehyde is
emitted in the smoke from cigarettes. About 1.5 mg of formaldehyde was
found in the total smoke from one cigarette, which was distributed
between the main and side stream in the ratio of 1:50, i.e., 30 µg in
the main stream (= inhaled smoke) and 1526 µg in the side stream
(Jermini et al., 1976; Klus & Kuhn, 1982). Other investigators measured
up to 73 µg of formaldehyde per cigarette in the main stream (Newsome
et al., 1965; Mansfield et al., 1977). Concentrations of 60-130 mg/m3
were measured in mainstream smoke. For an individual smoking 20 ciga-
rettes per day, this would lead to an exposure of 1 mg/day (Weber-
Tschopp et al., 1977). Exposure to sidestream smoke (or environmental
tobacco smoke) can be estimated from chamber measurements. Thus, in a
50-m3 chamber with one air exchange per hour, 6 cigarettes smoked in
15 min yield over 0.12 mg/m3 (WKI, 1982). Weber-Tschopp et al.
(1976) measured the yield of 5-10 cigarettes in a 30-m3 chamber with
0.2-0.3 air exchanges per hour as 0.21-0.35 mg/m3, which would be
about 0.05-0.07 mg/m3 at one air exchange per hour. This concentration
is in the same range as that likely to be found in the rooms of most
conventional buildings where there is no smoking (section 5.2). Levels
of formaldehyde emitted from combustion sources other than cigarette
smoke are presented in Table 20.
Table 20. Formaldehyde levels from combustiona
--------------------------------------------------------------------------------------------------------
Source Comments Emission rate Air change HCHO Reference
(g fuel/min) per h (mg/m3)
--------------------------------------------------------------------------------------------------------
Gas stove in test ventilation conditions:
kitchen, 27 m3 no stove vent or hood 0.25 0.40 Hollowell
hood vent (without fan) above stove 1.0 0.26 et al.
hood vent, fan at low speed (1979)
(1.4 m3/min) 2.5 0.14
hood vent, fan at high speed
(4 m3/min) 7.0 0.035
outdoor concentration during test 0.010
Undiluted exhaust gases: 10 Schmidt &
Götz (1977)
Household natural gas
appliances 6 Altshuller
Cooking range (oven) 4 et al.
Floor furnace 1.5 (1961)
Kerosine heaters: 27 m3 environmental chamber, 0.4
temp. < 26 °C
radiant (new) fired in chamber 3.13 5.1 5.1b Traynor
10-min warm-up outside chamber 3.16 4.0 et al.
(1983)
radiant (1 year old) 10-min warm-up outside 2.54 0.67
convection (new) fired in chamber 3.03 0.36
10-min warm-up outside chamber 3.0 1.3
convection fired in chamber 2.1 6.7
(5 years old) 10-min warm-up outside chamber 2.2 5.6
--------------------------------------------------------------------------------------------------------
Table 20 (contd).
--------------------------------------------------------------------------------------------------------
Radiant heater 21 m3 room, closed door, 3.6 0.5 0.025 Caceres
Radiant heater 3.6 1.0b et al.
Convection heater 2.7 0.9b (1983)
0.4b
Cigarette smoke 30 m3 climate chamber, 0.3
1 cigarette (1 min) 0.06 Weber-
3 cigarettes (2 min) 0.16 Tschopp
5 cigarettes (3 1/2 min) 0.29 et al.
10 cigarettes (7 min) 0.55 (1976)
15 cigarettes (10 1/2 min) 0.76
Cigarette smoke 45.8 m3 room, 5 subjects, Sundin
20 cigarettes smoked over 30 min: (1978)
original background level
level after 30 min 0.01
0.33
Cigarette smoke undiluted smoke 40-140 Auerbach
et al.
(1977)
--------------------------------------------------------------------------------------------------------
a From: Dept National Health Welfare Canada (1985).
b mg/h.
5.3 General Population Exposure
The possible routes of exposure to formaldehyde are inhalation,
ingestion, dermal absorption, and, rarely, blood exchange, as in dialy-
sis.
5.3.1 Air
The daily inhalation exposure for an average adult can be estimated
by assuming a respiratory volume of 20 m3/day, given the exposures
mentioned above, and making different assumptions about the duration of
exposure periods (Table 21). Average time estimates lead to the con-
clusion that people spend 60-70% of their time in the home, 25% at
work, and 10% outdoors. If it is assumed that normal work exposures are
similar to home exposures, the daily exposure resulting from breathing
is about 1 mg/day, with a few exposures of > 2 mg/day, and a maximum
of 5 mg/day; this compares favourably with the estimated range of
0.3-2.1 mg/day, based on the work of Kalinic et al. (1984), with esti-
mated weighted average exposures of 0.02-0.14 mg/m3.
Matsumura et al. (1985) determined the levels of exposure to for-
maldehyde of housewives by using personal air sampling apparatus
(Sampler: silica gel impregnated with triethanolamine, Hydrazine-
method). The highest exposure level was 0.311 mg/m3 (0.259 ppm) (3.73
mg/day), while the lowest was 0.011 mg/m3 (0.009 ppm) (0.13 mg/day).
The usual exposure range was 0.018-0.030 mg/m3 (0.015-0.025 ppm)
(0.22-0.36 mg/m3). The highest exposure level was that of a housewife
living in a newly constructed house, where irritation of the eyes and
throat, lachrymation, and cough were observed in the family.
Chemical toilet fluids, used in caravans, on camping sites, in
aeroplanes, and in boats often include formaldehyde. In an experiment,
a 10% formaldehyde solution (normally found on the market) was applied
in a 2 m3 toilet room (Reus, 1981a). The toilet bowl was filled with
1 1/2 litres of water and 110 ml of the disinfectant, giving a solution
of 0.75% formaldehyde. The ventilation rate was not determined, but
estimated to be 3-5 air changes per hour, temperature 20-22 °C. Air
concentrations of formaldehyde, which rose to 150-350 µg/m3 during
the filling of the toilet, gradually decreased within 1 h to 60-90 µg/m3 and
then remained constant. Closing the lid caused a further decrease to
< 20 µg/m3.
5.3.1.1 Smoking
Concentrations of 60-130 mg/m3, measured in mainstream smoke,
would lead to an average daily intake of 1 mg formaldehyde per day
(daily consumption: 20 cigarettes; WHO, 1987).
Formaldehyde produced by cigarettes can also mean considerable ex-
posure for the non-smoker through passive smoking, the more so since it
has been reported that the effects of gaseous formaldehyde are poten-
tiated by smoke particles and aerosols (Rylander, 1974; Weber-Tschopp
et al., 1977; WHO, 1987).
Table 21. Contribution of various atmospheric environments
to average exposurea
----------------------------------------------------------------
Source Average exposure
(mg/day)
----------------------------------------------------------------
Air
Ambient air (10% of the time) 0.02
Indoor air
Home (65% of the time)
- Conventional 0.5-2
- Prefabricated (particle board) 1-10
Work-place air (25% of the time)
- Without occupational exposureb 0.2-0.8
- Exposed occupationally to 1 mg/m3 5
- Environmental tobacco smoke 0.1-1.0
Smoking
20 cigarettes/day 1.0
----------------------------------------------------------------
a From: WHO (1987).
b Assuming the normal formaldehyde concentration in conventional
buildings.
5.3.2 Drinking-water
Concentrations in drinking-water are normally less than 0.1 mg/
litre, which means that, except for accidental ingestion of formal-
dehyde-contaminated water, intake is negligible (below 0.2 mg/day; WHO,
1987).
5.3.3 Food
The daily formaldehyde intake depends on the composition of the
meal and may range between 1.5 and 14 mg for an average adult (see
Table 14, section 5.1.4).
In a residue study of the Food Inspection Service in The
Netherlands, it was found that 53% of 162 samples of soft drinks,
alcoholic beverages, sugar-containing foodstuffs, such as marmalade,
and meat and meat products contained formaldehyde at levels exceeding
1 mg/kg. Up to 20% of samples contained levels exceeding 2 mg/kg;
levels in 15 samples of meat and meat products even exceeded 10 mg/kg,
with some reaching about 20 mg/kg. The source of the formaldehyde
could not be established for any of the cases (Nijboer, 1984). In an
additional study, the formaldehyde contents of meat and meat products
were analysed (Nijboer, 1985) and, in 62 out of 86 samples, were found
to exceed a level of 1 mg formaldehyde/kg. Levels in 50% of samples
were between 1 and 2 mg/kg and 22% exceeded 2 mg/kg with some levels
as high as 14-20 mg/kg. Again, no source for the formaldehyde residue
could be established.
5.3.4 Other routes of exposure
Dermal exposure and absorption occur through contact with cos-
metics, household products, disinfectants, textiles (especially of
artificial origin) and orthopaedic casts. Most of these exposures are
likely to remain localized (though gaseous formaldehyde will be avail-
able for inhalation). The estimates of the systemic absorption of for-
maldehyde through the entire epidermal layer and across the circulatory
layer, are negligible (Jeffcoat, 1984; Robbins et al., 1984; Bartnik et
al., 1985). Contact with liquid barriers, as in the eyes does not
appear to lead to absorption. There have been case reports of newborn
infants being exposed to formaldehyde-containing disinfectants in
incubators.
In certain rare events, formaldehyde in aqueous solution enters the
blood stream directly. These events are most likely to occur during
dialysis or in circulation-assisted surgery in which the dialysis ma-
chine and tubes that have been disinfected with formaldehyde, still
contain the compound because of adsorption or back wash, and it is then
introduced into the patient's bloodstream (Beall, 1985).
5.4 Occupational Exposure
In the work-place, exposure may be caused by either producing or
handling formaldehyde or products containing formaldehyde. Concen-
trations of formaldehyde in occupational settings in the USA were
reported by the Consensus Workshop on Formaldehyde (1984) (Table 22,
see also section 9.2).
Airborne formaldehyde concentrations in 7 funeral homes in 1980 in
the USA ranged from 0.12 to 0.42 mg/m3 during the embalming of non-
autopsied bodies and from 0.6 to 1.4 mg/m3 during the embalming of
autopsied bodies (Williams et al., 1984). In a study on formaldehyde
exposure in an embalming room, levels of up to 4.8 mg/m3 were found
when the exhaust ventilation system was not functioning (Anon.,
1980a,b).
Formaldehyde concentrations were determined in Dutch pathological
laboratories, under practical conditions, where a 4-6% solution of
formaldehyde in water was used. No detailed information on ventilation
is available, but a special ventilation system was applied at the
dissection table, where concentrations amounted to 75 µg/m3. A con-
centration of 195 µg/m3 was found in the cleaning section of the
laboratory (Reus, 1981).
Table 22. Formaldehyde monitoring data in occupational settingsa
--------------------------------------------------------------------------------------------------------
Industry Job or Exposure levels mg/m3 (ppm) Area or Number of Methodb Reference
work personal observa-
area range mean median monitor- tions
ing
--------------------------------------------------------------------------------------------------------
Formaldehyde production - 1.68 - personal - CT, IC NIOSH
production operator (1.4) (1980a)
laboratory - 1.57 - personal - CT, IC NIOSH
technician (1.31) (1980a)
Resin and plastic production - 1.67 - personal - CT, IC NIOSH
materials operator (1.39) (1980a)
production
resin plant 0.06-0.44 0.29 - area 8 BI, CT, NIOSH
(0.05-0.37) (0.24) GC (1976a)
resin plant 0.11-0.20 0.16 - area 2 BI, CO NIOSH
(0.09-0.17) (0.13) (1978a)
UF resin 0.14-0.66 - - area - SS, IC Herrick et
production (0.12-0.55) al. (1983)
(2 plants) 0.22-6.48 - - area - SS, IC Herrick et
(0.18-5.4) al. (1983)
0.24-0.89 - - area - SS, IC Herrick et
(0.2-0.74) al. (1983)
0.72-0.41 - - area - SS, IC Herrick et
(0.6-0.34) al. (1983)
UF resin 0.14-6.48 1.08 - personal 18 BI, CA NIOSH
production (0.12-5.4) (0.90) (1980b)
0.24-0.89 0.47 - personal 5 BI, CA NIOSH
(0.20-0.74) (0.39) (1980b)
0.72-0.41 0.23 - personal 5 BI, CA NIOSH
(0.06-0.34) (0.19) (1980b)
--------------------------------------------------------------------------------------------------------
Table 22 (contd).
--------------------------------------------------------------------------------------------------------
Industry Job or Exposure levels mg/m3 (ppm) Area or Number of Methodb Reference
work personal observa-
area range mean median monitor- tions
ing
--------------------------------------------------------------------------------------------------------
Textile finishing textile 0.05-0.88 0.37 - area, 11 CT, SP NIOSH
warehouse (0.04-0.73) (0.31) personal (1979a)
0.10-0.61 0.30 - area, 11 BI, SP NIOSH
(0.08-0.51) (0.25) personal (1979a)
textile < 0.12-1.56 - 0.96 area, 28 - NIOSH
facilities (< 0.1-1.3) (0.8) personal (1979b)
< 0.12-1.68 - 0.84 area, 15 - NIOSH
(< 0.1-1.4) (0.7) personal (1979b)
textile 0.13-1.60 0.83 0.77 personal 6 - NIOSH
manufacture (0.11-1.33) (0.69) (0.64) (1981)
0.18-1.44 0.64 0.54 area 13 NIOSH
(0.15-1.2) (0.53) (0.54) (1981)
Clothing permanent 0.18-0.46 0.37 - area 9 BI, I US DHEW
production press (0.15-0.38) (0.31) (1966)
0-3.24 0.89 - area 32 BI, I US DHEW
(0-2.7) (0.74) (1968)
warehouse 0.13-0.68 0.47 0.44 personal 13 - NIOSH
(0.11-0.57) (0.39) (0.37) (1979a)
0.05-0.23 0.14 0.18 area 9 - NIOSH
(0.04-0.19) (0.12) (0.15) (1979a)
sewing 0.61-1.09 0.86 0.85 personal 16 - NIOSH
machine (0.51-0.91) (0.72) (0.71) (1979a)
operators 0.36-2.16 1.44 1.44 personal 41 - NIOSH
(0.3-1.8) (1.2) (1.2) (1979a)
clothing 0.006-1.14 0.08 0.065 personal 40 - NIOSH
pressers (0.005-0.95) (0.07) (0.054) (1976a)
--------------------------------------------------------------------------------------------------------
Table 22 (contd).
--------------------------------------------------------------------------------------------------------
Plywood particle- all workers - 1.2-3.0 - area - - NIOSH
board production (1-2.5) (1979b)
Wood furniture particle 0.01-0.3 0.14 - area 11 BI, CA Herrick et
manufacture board (0.008-0.25) (0.12) al. (1983)
veneering 1.08-7.68 3.30 - area - BI, CA Herrick et
(0.9-6.4) (2.75) al. (1983)
0.24-0.66 0.48 - area 9 BI, CA Herrick et
(0.2-0.55) (0.40) al. (1983)
0.24-3.0 0.84 - area 13 BI, CA Herrick et
(0.2-2.5) (0.70) al. (1983)
Plastic moulding injection 0.01-0.12 0.044 - personal 9 CA NIOSH
mold (0.01-0.1) (0.037) (1973a)
area samples 0.01-0.64 0.24 - area 8 CA NIOSH
(0.01-0.53) (0.20) (1973a)
operators < 2.4 < 2.4 < 2.4 personal 28 DT NIOSH
(< 2) (< 2) (< 2) (1973a)
near grinder 2.4-4.8 3.6 3.6 area 3 DT NIOSH
hopper (2-4) (3) (3) (1973a)
sand mould 0.12-0.84 0.37 0.24 personal 28 - NIOSH
production (0.1-0.7) (0.31) (0.2) (1976a)
ND-1.32 0.20 0.12 area 29 - NIOSH
(ND-1.1) (0.17) (0.1) (1976a)
Paper and paper- paper 0.05-0.19 0.10 - personal 15 BI, CT NIOSH
board manufacture treatment (0.04-0.16) (0.08) CA (1976b)
resin) 0.04-0.08 0.07 - area 7 BI, CT, NIOSH
impregnated (0.03-0.07) (0.06) CA (1976b)
0.01-0.28 0.06 - personal 30 BI, CT, NIOSH
(0.01-0.23) (0.05) CA (1976b)
--------------------------------------------------------------------------------------------------------
Table 22 (contd).
--------------------------------------------------------------------------------------------------------
Industry Job or Exposure levels mg/m3 (ppm) Area or Number of Methodb Reference
work personal observa-
area range mean median monitor- tions
ing
--------------------------------------------------------------------------------------------------------
Paper and paper-
board manufacture
(contd). 0.02-0.34 0.06 - personal 10 BI, CT, NIOSH
(0.02-0.28) (0.05) CA (1976b)
treated 0.17-1.19 - 0.70 area 64 - NIOSH
paper (0.14-0.99) (0.59) (1979b)
products 0.17-1.08 - 0.41 personal 37 - NIOSH
(0.14-0.90) (0.34) (1979b)
coating < 0.01-3.6 1.2 0.01 area 7 - NIOSH
preparation (< 0.01-3) (1.0) (0.01) (1980a)
0.96-0.50 0.61 0.50 area 4 - NIOSH
(0.8-0.42) (0.51) (0.42) (1980a)
Foundries (steel, bronze 0.29-0.96 0.64 0.66 personal 4 BI, CA NIOSH
iron, and non- foundry, (0.24-0.80) (0.53) (0.55) (1976c)
ferrous) core machine 0.14-0.83 0.47 0.47 area 11 BI, CA NIOSH
operators (0.12-0.69) (0.39) (0.39) (1976c)
iron foundry, < 0.02-22.0 - 0.52 personal 14 - NIOSH
core machine (0.02-18.3) (0.43) (1979b)
operators 0.08-0.40 0.19 - personal 3 BI, CA NIOSH
(0.07-0.33) (0.16) (1973b)
moulding 0.04-0.16 0.11 - personal 6 BI, CO NIOSH
(0.03-0.13) (0.09) (1977a)
0.08-0.94 0.25 - area 6 BI, CO NIOSH
(0.07-0.78) (0.21) (1977a)
Rubber hose pro- - ND-0.05 0.05 - personal 10 BI, CO NIOSH
duction (ND-0.04) (0.04) (1977b)
--------------------------------------------------------------------------------------------------------
Table 22 (contd).
--------------------------------------------------------------------------------------------------------
Asphalt shingle producers 0.04-0.08 0.06 0.06 area 2 BI, CO NIOSH
production (0.03-0.07) (0.05) (0.05) (1978b)
Fibreglass insul- installers 0.008-0.04 0.028 0.023 personal 13 - NIOSH
ation (0.007-0.033) (0.023) (0.019) (1980a)
(TWA)c
Urea-formaldehyde suburban 0.08-2.4 - - - - IC Herrick et
foam insulation shopping (0.07-2) al. (1983)
dealing and in- centre 0.96-1.92 1.26 - area 36 BI, CA NIOSH
stallation insulated (0.8-1.6) (1.05) (1979b)
with UF foam 0.36-3.72 1.73 - area 30 CT, IC NIOSH
(0.3-3.1) (1.44) (1979b)
< 0-6.36 1.87 - area 16 DT NIOSH
(< 0.5-3) (1.56) (1979b)
Fertilizer manu- - 0.24-2.28 1.08 - personal, 11 - NIOSH
facturing (0.2-1.9) (0.9) area (1979b)
Mushroom farming - < 0.61-12+ 3.22 - area 12 DT NIOSH
(0.51-10+) (2.68) (1980b)
ND-3.24 personal 3 CT, IC NIOSH
(ND-2.7) (1980b)
ND-5.92 - - area 3 CT, IC NIOSH
(ND-4.93) (1980b)
Funeral homes embalmers 0.1-6.3 0.89 - area 187 CA Kerfoot &
(0.09-5.26) (0.74) Mooney
(1975)
0.24-4.79 1.32 0.65 area 8 CT NIOSH
(0.20-3.99) (1.1) (0.54) personal (1980c)
1.56-4.72 3.24 2.99 area 5 CT NIOSH
(1.30-3.99) (2.7) (2.49) personal (1980c)
Pathology autopsy room 0.07-9.5 5.76 - area 10 BI, CA Covino
(0.06-7.9) (4.8) (1979)
2.64-9.5 5.22 - area 6 - NIOSH
(2.20-7.9) (4.35) (1979b)
--------------------------------------------------------------------------------------------------------
Table 22 (contd).
--------------------------------------------------------------------------------------------------------
Industry Job or Exposure levels mg/m3 (ppm) Area or Number of Methodb Reference
work personal observa-
area range mean median monitor- tions
ing
--------------------------------------------------------------------------------------------------------
Biology teaching laboratory 3.30-17.76 9.96 - area 8 BI, CA US EPA
(2.75-14.8) (8.3) (1981)
Hospital laboratory 2.64-2.76 2.70 personal 2 BI Blade
(2.2-2.3) (2.25) (1983)
2.28 (1.9) - personal 1 CT Blade
2.64 (2.2) 2.4 (2) area 2 CT (1983)
Government laboratory 2.88 (2.4) - personal 1 CT Blade
0.96 (0.8) - area 1 CT (1983)
Hospital dialysis ND-1.08 0.50 area 9 CT Blade
unit (ND-0.90) (0.42) (1983)
0.32-0.76 0.49 personal 5 CT Blade
(0.27-0.63) (0.41) (1983)
0.05-0.60 0.61 area CEA Blade
(0.04-0.50) (0.51) (1983)
Animal dissection laboratory < 0.46-1.25 - personal 15 CA Blade
(< 0.38-1.04) (1983)
0.06-0.48 0.18 area 6
(0.05-0.40) (0.15)
0.13-0.22 0.22 area 3 CEA Blade
(0.11-0.29) (0.18) (1983)
Garment manufac- - < 0.17-0.76 0.28-0.40 personal 40 CT Blade
turing (3 plants) (< 0.14-0.63) (0.23-0.33) (1983)
< 0.04-0.48 0.23-0.31 area 43 CT Blade
(< 0.03-0.40) (0.19-0.26) (1983)
0.04-0.48 0.25 area 43 BI Blade
(0.03-0.40) (0.21) (1983)
--------------------------------------------------------------------------------------------------------
Table 22 (contd).
--------------------------------------------------------------------------------------------------------
Garment manufac-
turing (contd)
0.06-1.34 0.55 area 42 CEA Blade
(0.05-1.2) (0.46) (1983)
Chemical manu- - 0.05-1.92 0.66 - personal 3 BI Blade
facturing (0.04-1.6) (0.55) (1983)
0.04-0.52 0.20 - area 5 BI Blade
(0.03-0.43) (0.17) (1983)
Glass manufac- - 0.50 (0.42) 0.50 - personal 1 CT Blade
facturing (0.42) (1983)
0.54-0.80 0.65 - area 2 CT Blade
(0.45-0.64) (0.54) (1983)
Hospital work - 0.44-0.88 0.66 - area 2 BI Blade
(0.37-0.73) (0.56) (1983)
Paraformaldehyde - < 0.30-1.02 0.66 - personal 10 CA Blade
packaging (< 0.25-0.85) (0.55) (1983)
0.34-4.08 1.40 - area 8 CEA Blade
(0.28-3.4) (1.17) (1983)
Office work - 0.02-0.14 0.07 - area 39 BI Blade
(3 locations) (0.02-0.12) (0.06) (1983)
< 0.05 < 0.05 - area 9 CT Blade
(< 0.04) (< 0.04) (1983)
--------------------------------------------------------------------------------------------------------
Table 22 (contd).
--------------------------------------------------------------------------------------------------------
Industry Job or Exposure levels mg/m3 (ppm) Area or Number of Methodb Reference
work personal observa-
area range mean median monitor- tions
ing
--------------------------------------------------------------------------------------------------------
Autopsy rooms resident - 1.90d personal 10 CA Makar et
(1.58) al. (1975)
pathologist - 1.50d personal 9 CA
(1.24)
technician - 0.68d personal 2 CA Makar et
(0.57) al. (1975)
assistants 0.16-16.28 0.86 area 23 CA
(0.13-13.57) (0.72)
--------------------------------------------------------------------------------------------------------
a From: Consensus Workshop on Formaldehyde (1984).
b Abbreviations for analytical procedures:
AA = acetylacetone.
BI = bisulfite impingers.
CA = chromotropic acid procedure.
CL = chemiluminescence procedure.
CO = colorimetric analysis.
CT = charcoal tubes.
SS = solid sorbents.
DT = Draeger tubes.
FS = Fourier transform spectrometer.
GC = gas chromatography.
IC = ion chromatography.
MB = MBTH procedure.
SP = spectrophotometric procedure.
CEA = CEA instruments Model 555.
c TWA = time-weighted average.
d Average.
6. KINETICS AND METABOLISM
6.1 Absorption
6.1.1 Inhalation
6.1.1.1 Animal data
Eight male F-344 rats were exposed to 17.3 mg formaldehyde/m3
(14.4 ppm) by nose only inhalation for 2 h, and the blood was collected
immediately after exposure. Formaldehyde concentrations in the blood
were determined by gas chromatography/mass spectrometry. The blood of 8
unexposed rats was collected and analysed in the same manner. Measured
formaldehyde concentrations (mg/kg blood) were: exposed, 2.25 ± 0.07;
controls, 2.24 ± 0.07 (mean ± SE) (Heck et al., 1985).
Under normal conditions, absorption is expected to occur in the
upper respiratory tract (nasal passages in obligate nose-breathers;
trachea, bronchi in oral breathers) where first contact occurs (Heck
et al., 1983).
Absorption through the upper respiratory tract was estimated to be
100% at all respiratory rates tested. Detailed studies on the distri-
bution of 14C-formaldehyde in the rat nasal cavity have confirmed that
it is absorbed primarily in the upper respiratory system. Following a
6-h exposure by inhalation, the amount of 14C-formaldehyde absorbed
appeared to be approximately proportional to the airborne concen-
tration. The amount retained did not appear to vary following pre-
exposure (Heck et al., 1982).
Chang et al. (1983) reported studies on the effects of inhaled for-
maldehyde vapour on respiratory minute volumes in mice and rats. The
results showed that both rats and mice responded to formaldehyde inha-
lation by a reduction in their respiratory rates and minute volumes.
However, mice responded to lower formaldehyde concentrations than rats.
For example, respiratory rates were reduced by 50% at 7.2 mg/m3
(6 ppm) in mice and 18 mg/m3 (15 ppm) in rats. Rats developed some
tolerance to formaldehyde during exposure. Both rats and mice
pretreated with 18 mg formaldehyde/m3 (15 ppm) were slightly more
sensitive to respiratory-rate depression, but pretreated rats compen-
sated for the decrease in respiratory rate by an increase in tidal
volume. Thus, following pretreatment, the difference in sensitivity
between the two species became more marked. As a result, mice were able
to minimize the inhalation of formaldehyde more efficiently than rats,
so that, at 18 mg/m3 (15 ppm), the nasal mucosa in mice was exposed to
approximately one-half of the dose of formaldehyde to which the rats
were exposed. This species difference contributes to the differences
in respiratory tract toxicity from inhaled formaldehyde.
The respiratory retention of inhaled formaldehyde (0.15-0.35 µg/ml)
was studied in 4 sedated dogs by enforced ventilation (Egle, 1972).
The percentage uptake was calculated by determining the amount inhaled
by means of a respirometer and the amount recovered after exhaling into
a collection bag (Method: MBTH, Hauser & Cummins, 1964). Absorption
was determined to be near 100%, even when the ventilation rate of the
dogs was increased to 20 litre/min.
6.1.1.2 Human Data
In human volunteers exposed to 2.3 mg formaldehyde/m3 (1.9 ppm)
for 40 min, there was no significant difference between pre- and post-
exposure formaldehyde levels in the blood (2.77 ± 0.28 µg and
2.61 ± 0.14 µg/100 ml, respectively). Individual human subjects dif-
fered in terms of their blood-formaldehyde levels and, in some sub-
jects, there were significant differences between formaldehyde concen-
trations in the blood before and after exposure suggesting that blood-
formaldehyde concentrations may vary with time (Heck et al., 1985).
In an earlier study, Einbrodt et al. (1976) measured the formate
levels in blood and urine following formaldehyde inhalation. They con-
cluded that the determination of formic acid is appropriate for esti-
mating previous formaldehyde exposure. This could not be confirmed
using modern analytical methods (Triebig et al., 1980, 1986; Bernstein
et al., 1984). It has been demonstrated that biological monitoring of
formaldehyde exposure is not a feasible technique for exposure levels
of less than 0.6 mg/m3 (0.5 ppm) (Gottschling et al., 1984).
6.1.2 Dermal
In in vitro experiments, Usdin & Arnold (1979) studied the transfer
of 14C-formaldehyde into guinea-pig skin. Aqueous 14C-formaldehyde
(0.20 µg) was applied in diffusion cells (area, 2 cm2), and some
were occluded to avoid uncontrolled evaporation of formaldehyde.
Under both occluded and non-occluded conditions, 14C was found on
and in the dehaired skin (up to 0.8% of the initial dose), and small
amounts (0.4% of the initial dose) were excreted in the urine.
However, the labelled material found was not identified, and it is not
known whether or not it was formaldehyde.
In another in vitro experiment, the permeability of human skin to
formaldehyde was examined using excised skin in a flow-through dif-
fusion cell. The rate of resorption was determined by measuring the
amount of substance found in the receptor fluid beneath the skin at
steady-state. The rates of resorption were: formaldehyde from a concen-
trated solution of formalin, 319 µg/cm2 per h, formaldehyde from a
solution of 10% formalin in phosphate buffer, 16.7 µg/cm2 per h
(Loden, 1986).
An ointment containing 0.1% of 14C-formaldehyde was applied to
the shaved backs of rats by Bartnik et al. (1985). Three to 5% of the
14C-formaldehyde was found to have been absorbed within 48 h.
14C-formaldehyde or dimethyloldihydroxyethyleneurea (DMDHEU)
were incorporated into cotton. Patches were applied to the shaved backs
of rabbits for a period of 48 h; 0.09-2.61% of the total 14C contained
in the patches was found in the skin. Other tissues and organs
showed only low levels of radioactivity (0.001-0.005% of the total
14C (Robbins et al., 1984).
Twenty-four hours after dermal application of 0.4-0.9 µg 14C-
formaldehyde/cm2 in 5 male monkeys, most of the dose had been lost,
mainly by evaporation from the skin (52%) or was bound (34%) to the
surface layers of the skin at the application site. Percutaneous pen-
etration was very low, calculated to be, at the most, 0.5% of the
applied dose. The total body burden of a necropsied monkey, 24 h after
dermal dosing, was 0.2% of the dose, confirming that aqueous formal-
dehyde does not penetrate the skin to any appreciable degree, even when
applied directly to it (Jeffcoat, 1984).
6.1.3 Oral
Following oral exposure (gavage) of 5 anaesthetized dogs to formal-
dehyde (70 mg/kg), formate levels in the blood increased rapidly. How-
ever, fifteen minutes after treatment, all the dogs vomited making
quantitative determinations impossible (Malorny et al., 1965).
6.2 Distribution
The normal values of blood-formaldehyde have been determined in
both rats and human beings. In rats, the analyses were performed by
gas chromatography/mass spectrometry using a stable isotope dilution
technique (Heck et al., 1982); values of 2.24 ± 0.07 mg/kg (mean ± SE)
were found.
The mean formaldehyde concentration in the blood of 6 human
volunteers (4 males, 2 females) was 2.61 ± 0.14 mg/kg (mean ± SE) (Heck
& Casanova-Schmitz, 1984) (see section 6.1.1.2).
Malorny et al. (1965) intravenously infused 0.2 mol formaldehyde
into dogs and cats; McMartin et al. (1977) performed similar infusions
in cynomolgus monkeys. There was no accumulation of formaldehyde in the
blood, because of its rapid conversion to formate.
The disposition of radioactive formaldehyde was studied in A/J mice
to determine its elimination and to assess its accumulation in tissues.
Mice were dosed ip with 14CH2O at 6 mg/kg or 100 mg/kg body weight.
Most of the dose (70-75%) was excreted as 14CO2 within 4 h, but an
additional 10% of the dose was eliminated as 14CO2 in 24 h. The rate
of 14CO2 excretion in mice given 14CH2O was slower than the rate
of 14CO2 excretion in mice given an equivalent dose (100 mg/kg) of
formate (HCOOH), the obligatory intermediate in the oxidation of for-
maldehyde to carbon dioxide. These results suggest that formaldehyde
might accumulate in tissues. To assess this possibility, whole-body
levels of 14CH2O were determined by the dimedone precipitation
method following a dose of 100 mg/kg. The elimination half-time of for-
maldehyde was calculated to be 100 min, with a rate constant of 0.42/h.
However, several rate constants were observed, 80% of the dose being
recovered as formate at 30 min. At 2 h, the level of 14CH2O in
the plasma was 1.07 ± 0.25 mg/litre, and the liver level was 1.7 ±
0.87 mg/kg. Levels of 14CH2O in other tissues were similar to that
in the liver. This level of 14CH2O is at least 50% lower than the
endogenous level of formaldehyde that has been reported. These results
suggest that there is more than a single formaldehyde pool in mice but
that, nevertheless, it does not accumulate in tissues at levels that
are significant relative to the endogenous tissue level (Billings et
al., 1984).
Whole-body autoradiography of mice, sacrificed 5 min after an iv
injection of 14C-formaldehyde, showed localization of radioactivity,
primarily in the liver and, to a lesser extent, in the kidneys. Follow-
ing a survival time of 30 min or more, radioactivity appeared in the
tissues with a high cell turnover (blood-forming organs, lymphoid sys-
tem, gastrointestinal mucosa) and in those with a high rate of protein
synthesis (exocrine pancreas, salivary glands) (Johansson & Tjalve,
1978).
Following a 6-h inhalation exposure of rats to up to 18 mg/m3
(15 ppm) 14C-formaldehyde, radioactivity was extensively distributed
in other tissues, the highest concentrations occurring in the oesoph-
agus, followed by the kidney, liver, intestine, and lung, indicating
that absorbed 14C-formaldehyde and its metabolites were rapidly re-
moved by the mucosal blood supply. Studies on distribution and kinetics
indicated that inhaled formaldehyde is extensively metabolized and
incorporated (Heck et al., 1982).
DNA, RNA, protein, and lipid fractions of liver and spleen tissues
of rats showed significantly elevated levels of 14C incorporation
after a single ip injection of 72 mg 14C-formaldehyde (14.7 µCi/kg)
(Upreti et al., 1987).
The retention of formaldehyde gas in the nasal passages of anaes-
thetized male F-344 rats exposed in a nose-only system to 14C-formal-
dehyde at 2.4-60 mg/m3 for 30 min was studied by Patterson et al.
(1986). More than 93% was retained, regardless of airborne concen-
trations.
In order to localize absorption and distribution within the nasal
cavity, rats and mice, not previously exposed or pretreated, were
exposed to 18.0 mg 14C-formaldehyde/m3 (15 ppm) for 6 h and prepared
for whole-body autoradiography. Formaldehyde-associated 14C was
heavily deposited in the anterior nasal cavity in both rats and mice.
The amount of radioactivity was well correlated with the distribution
of lesions in exposed animals. However, the radioactivity may represent
metabolically incorporated material rather than covalently bound for-
maldehyde. No differences in the distribution of formaldehyde were
observed between rats and mice (Swenberg et al., 1983).
6.3 Metabolic Transformation
The overall metabolism of formaldehyde is summarized in Fig. 3.
The oxidation into formic acid and carbon dioxide, the reaction
with glutathione, and the covalent linkage with proteins and nucleic
acids, which are partly reversible, are of importance. The covalent
linkage to formaldehyde cannot be directly determined, since radio-
active formaldehyde is also incorporated into the DNA via the one-
carbon metabolism.
In studies on several species, including human beings, formaldehyde
underwent rapid biotransformation, immediately after resorption, and,
therefore, could not be traced in tissue (Simon, 1914; Malorny et al.,
1965; Rietbrock, 1965; Einbrodt et al., 1976; Delbrück et al., 1982).
Heck & Casanova-Schmitz (1984) showed that blood-formaldehyde concen-
trations did not rise in human volunteers even immediately after
inhalation exposure.
Kitchens et al. (1976) summarized the chemical reactions in bio-
logical systems as: (a) hydration in the presence of water; (b) reac-
tions with the active hydrogen of ammonia, amines, or amides, resulting
in the formation of stable methylene bridges; such reactions are
important, because of the ubiquity of nitrogen compounds; and (c) reac-
tions with active hydrogen (thiols, nitroalkanes, hydrogen cyanide,
phenol).
Formaldehyde may be formed endogenously (Hutson, 1970) after
contact with xenobiotics; 18 chemicals have been shown to be metab-
olized by the nasal microsomes of rats to produce formaldehyde (Dahl &
Hadley, 1983). Formaldehyde is a normal metabolite in mammalian
systems. It is rapidly metabolized to formate (Malorny et al., 1965),
which is partially incorporated via normal metabolic pathways into the
one-carbon pool of the body or further oxidized to carbon dioxide.
Formaldehyde also reacts with proteins (French & Edsall, 1945) and
nucleic acids (Haselkorn & Doty, 1961; Lewin, 1966; Collins & Guild,
1968; Feldman, 1973; Chaw et al., 1980); it reacts with single-strand
DNA, but not with double-stranded DNA. This link is reversible. Only
formaldehyde cross-links of DNA and protein are stable (Brutlag et al.,
1969) (section 8.5). The biological reactions and metabolism of formal-
dehyde are shown in Fig. 4.
The oxidation of absorbed formaldehyde to formic acid is catalyzed
by several enzymes (Strittmatter & Ball, 1955). The most important
enzyme is the NAD-dependent formaldehyde dehydrogenase, which requires
reduced glutathione (GSH) as a cofactor. Thus, exogenous formaldehyde
becomes a source for the so-called one-carbon pool in intermediary
metabolism. Sources of formate are presented in Fig. 5.
There are at least 7 enzymes that catalyze the oxidation of formal-
dehyde in animal tissues, namely aldehyde dehydrogenase, xanthinoxi-
dase, catalase, peroxidase, glycerinaldehyde-3-phosphate dehydrogenase,
aldehyde oxidase, and a specific DPN-dependent formaldehyde dehydrogen-
ase (Cooper & Kini, 1962).
6.4 Elimination and Excretion
As discussed in section 6.3, absorbed formaldehyde is metabolized
rapidly to formate or enters the one-carbon pool to be incorporated
into other molecules. Besides this, there are two pathways of final
elimination via exhalation or renal elimination (Fig. 3). Du Vigneaud
et al. (1950) administered 14C-formaldehyde subcutaneously to rats and
found 81% of the radioactivity as carbon dioxide; a small amount was
found in choline. Neely (1964) administered formaldehyde intraperito-
neally to rats; 82% of the radiolabel was recovered as carbon dioxide
and 13-14% as urinary methionine, serine, and a cysteine adduct.
Even after high formaldehyde uptake, the elimination of formate via
the kidneys of rats is virtually negligible (Delbrück et al., 1982).
Robbins et al. (1984) injected 14C-formaldehyde (100 µCi in a volume
of 1 ml) in rabbits. Four hours after administration, 28.5% of the
total dose of radioactivity was expired and 37%, after 48 h. By 48 h,
4.1% of the radioactivity had been excreted in the urine; significant
levels or radioactivity were detected in the liver (2.4%), kidney
(0.6%), and blood (2.2%).
6.5 Retention and Turnover
Elimination of formate is slower than its formation from absorbed
formaldehyde and depends on the species. Stratemann et al. (1968)
found a relationship between folate level shown in two biological test
systems and the half-life of formic acid in the plasma of some mammals
(Table 23).
Malorny et al. (1965) infused 0.2 mol formaldehyde intravenously
into dogs; the plasma half-life for formate ranged between 80 and
90 min, and formaldehyde could not be detected. In similar studies on
cynomolgus monkeys, by McMartin et al. (1979), infusing intravenously
1 mmol/kg over a 3-4 min period the blood half-life of formaldehyde was
estimated to be 1.5 min. Rietbrock (1969) administered 1.17 mmol
formaldehyde/kg iv to rats, guinea-pigs, rabbits, and cats, and found
the plasma half-life to be 1 min. The half-life of formate in human
beings given 50-60 mg Na-formate/kg, body weight orally, was 45 min
(Malorny 1969).
Table 23. Relationship between folate level and the
half-life of formic acid in plasmaa
--------------------------------------------------------------
Species Number Folate activity (ng/ml) Formate
of half-life
analyses L. casei Strept. faec. (min)
--------------------------------------------------------------
Man 11 15.5 ± 2.2 6.6 ± 0.7 55
Dog 37 15.5 ± 1.7 6.1 ± 0.9 77
Rabbit 17 49.2 ± 6.9 15.2 ± 1.4 32
Rat 21 126 ± 16.6 37.8 ± 8.9 12
--------------------------------------------------------------
a From: Stratemann et al. (1968).
7. EFFECTS ON ORGANISMS IN THE ENVIRONMENT
7.1 Microorganisms
Formaldehyde is used as a disinfectant to kill viruses, bacteria,
fungi, and parasites and has found wide use as a fumigant (section
3.2.2).
It produces mutagenic effects in prokaryotic and lower eukaryotic
test systems (Table 31, and section 8.6).
In a population of Aerobacter aerogenes , treatment with
50 µg formaldehyde/ml of medium produced a reversible change in the
base ratio of non-ribosomal RNA and induced enzymes capable of metab-
olizing formaldehyde at an increased rate (Neely, 1966).
Approximately 20-40% of the total nitrogen in most surface soils is
in the form of amino acids. Because of the importance of amino acids
as a nitrogen source for plant and microbial growth, Frankenberger &
Johanson (1982) studied the enzyme (EC 4.3.1.3) that catalyzes the
deamination of L-histidine in soils; treatment with formaldehyde mark-
edly inhibited its activity. Negative effects on the biological proper-
ties of the soil owing to increased doses of urea-formaldehyde ferti-
lizers have been reported by Rakhmatulina et al. (1984).
Berestetskii et al. (1981) found that formaldehyde was one of the
volatile compounds formed in the early stages of plant residue decompo-
sition in the soil. Kanamura et al. (1982) isolated a microorganism
(genus Hyphomicrobium ) from the soil that can use formaldehyde as the
only source of carbon. Furthermore, formaldehyde has a significant
role in the complex batch growth behaviour of a methanol-utilizing
bacterium ( Methylomonas ) (Agrawal & Lim, 1984).
The bacterial content of the soil near industrial enterprises
polluted with formaldehyde was 28-40 million bacteria/kg polluted soil;
the level in control areas was 900 million bacteria/kg soil. There is
no information on other pollutants or concentrations (Zhuravliova,
1969). Species of Pseudomonas were able to assimilate formaldehyde and
formate (Grabinska-Loniewska, 1974). Hingst et al. (1985) studied the
microorganism contents of sewage samples; species of Pseudomonas
survived a 30-min exposure to formaldehyde at 5 g/kg (admixture to
sewage samples).
Exposure to 2.4 mg formaldehyde/m3 for 24 h killed all spores from
pure cultures of various species of Aspergillus , Scopulariopsis , and
Penicillium crustosum (Dennis & Gaunt, 1974).
The phytopathogenic fungi Fusarium oxysporum , lycopersici , and
Rhizoctonia solani were completely eradicated after exposure for
30 min to an aqueous solution of formaldehyde at 4-5 g/litre. When
tested in tuff (a granular plant growth medium of volcanic rock
origin), the effectiveness of formaldehyde was lower compared with the
corresponding amounts in aqueous solutions (Sneh et al., 1983).
7.2 Aquatic Organisms
The acute toxicity of formaldehyde for various species of aquatic
organisms is shown in Table 24.
Many early studies conducted to determine the toxicity of formal-
dehyde and safe levels for therapeutic treatment against fungal infec-
tions and ectoparasites have been reported. This type of study is
difficult to evaluate with respect to environmental hazard because of
very short exposure periods and the way the data are presented.
From the data shown in Table 24, it appears that formaldehyde has a
relatively low toxicity for fish, 96-h LC50 values being higher than
10 mg/litre in all cases.
The toxic effects of formaldehyde on fresh-water trout and salmon
included changes in gill function, hypochloraemia, depressed plasma-
calcium and carbon dioxide, reduced blood pH, and decreased oxygen con-
sumption (Wedemeyer, 1971). Effects in rainbow trout occurred rapidly
after a 1 h exposure at 200 mg/litre, and ca. 24 h was required for
recovery (Wedemeyer & Yasutake, 1974). In rainbow trout and Atlantic
salmon, formalin treatment caused increased blood-haemoglobin, packed
cell volume, blood-glucose levels, and plasma-protein concentrations
(Nieminen et al., 1983). The toxicity of formaldehyde for rainbow
trout was increased by high water temperature, soft water, and high pH
levels (Bills et al., 1977).
Algae and some invertebrates seem to be more susceptible to formal-
dehyde. Acute toxicity occurs in green algae at formaldehyde concen-
trations of 0.3-0.5 mg/litre ( Scenedesmus sp. ), in several species of
protozoa, at 4.5-22 mg/litre, in Daphnia , at 2-20 mg/litre (EC50) and
in Cyprinodopris species at 0.42 mg/litre (96-h EC50). Other invert-
ebrates differ widely in their responses to formalin (Table 25).
For amphibia, the 24-, 48-, and 72-h LC50 values for larva of the
frog, Rana pipiens , were 8.4, 8.0, and 8.0 mg formaldehyde/litre, with
a 72-h LC100 at 11.4 mg/litre. Tadpoles of the bullfrog, Rana
catesbeiana , were more resistant, having 24-, 48-, and 72-h LC50
values of 20.1, 17.9, and 17.9 mg/litre, respectively, with a 72-h
LC100 of 30.4 mg formaldehyde/litre. In toad larvae ( Bufo sp. ) the
72-h LC50 and LC100 values were 17.1 and 19.0 mg/litre, respectively
(Helms, 1964). Carmichael (1983) exposed tadpoles of Rana berlandieri
to formalin for 24 h and found that no mortality occurred at concen-
trations < 6.0 mg formaldehyde/litre, but at 9.2, 13.6, 20.4, and
30.5 mg formaldehyde/litre, mortality was 13, 35, 78, and 100%,
respectively.
7.3 Terrestrial Organisms
Persson (1973) studied the influence of formalin on the eggs and
larvae of the cattle parasites Ostertagia ostertagia and Cooperia
oncophora in liquid cattle manure. A 1% solution destroyed the eggs
and a 5% solution affected the larvae. It also had a negative effect
on the germination and growth of crops fertilized with the manure.
Table 24. Acute toxicity of formaldehyde for some aquatic organisms (static bioassay)
--------------------------------------------------------------------------------------------------------
Organism/species Temperature pH Hardness Duration (LC50) Reference
( °C) degree of ex- (mg/litre)
posure (h)
--------------------------------------------------------------------------------------------------------
Algae
Scenedesmus quadricauda - 7.5 12 - 0.3 Bringmann & Kühn
(1960)
Scenedesmus 27 7.5-7.8 12 24 0.4 Bringmann & Kühn
(1980a)
Bacteria
Escherichia coli 25 7.5-7.8 - - 1 Bringmann & Kühn
(1960)
Pseudomonas fluorescens 25 7.5-7.8 - - 2 Bringmann & Kühn
(1960)
Protozoa
Chilomonas paramaecum - 6.9 - 48 4.5 Bringmann et al.
(1980)
Mikroregma 27 7.5-7.8 12 24 5 Bringmann & Kühn
(1980b)
Uronema parduczi - 6.9 - 20 6.5 Bringmann & Kühn
(1980b)
Entosiphon sulcatum 25 6.9 - 72 22 Bringmann (1978)
Water fleas
Daphnia magna 27 7.5-7.8 12 24 2 Corstjens &
Monnikendam (1973)
Daphnia magna 23 7.5 12 48 2 Corstjens &
Monnikendam (1973)
--------------------------------------------------------------------------------------------------------
Table 24 (contd).
--------------------------------------------------------------------------------------------------------
Water fleas (contd).
Daphnia magna (IRCHA) - 8 16 24 42 Bringmann & Kühn
(1982)
Daphnia magna 20-22 7.6-7.7 16 24 52 Bringmann & Kühn
(1977)
Daphnia magna - - - 24 100-1000 Dowden & Bennett
(1965)
Fish
Black bullhead 12 6.5-9.5 8 96 62.1a Bills et al. (1977)
- fingerling -
Channel catfish 12 6.5 8 96 65.8a Bills et al. (1977)
- fingerling -
Bluegill 12 6.5 8 96 100a Bills et al. (1977)
- fingerling -
Lake trout 12 6.5 8 96 100a Bills et al. (1977)
- fingerling -
Smallmouth bass 12 6.5 8 96 136a Bills et al. (1977)
( M. dolomieuri)
- fingerling -
Largemouth bass 12 6.5 8 96 143a Bills et al. (1977)
( M. salmoides)
- fingerling -
Atlantic salmon 12 6.5 - 96 173 McKim et al. (1976)
--------------------------------------------------------------------------------------------------------
Table 24 (contd).
--------------------------------------------------------------------------------------------------------
Organism/species Temperature pH Hardness Duration (LC50) Reference
( °C) degree of ex- (mg/litre)
posure (h)
--------------------------------------------------------------------------------------------------------
Fish (contd).
Atlantic salmon 12 6.5 8 3 564a Bills et al. (1977)
(fingerling) 12 6.5 8 6 336a Bills et al. (1977)
12 6.5 8 24 156a Bills et al. (1977)
12 6.5 8 96 69.2 Bills et al. (1977)
Green sunfish 12 - - 96 173 McKim et al. (1976)
Green sunfish 12 6.5 8 24 129a Bills et al. (1977)
(fingerling) 12 6.5 8 96 69.2a Bills et al. (1977)
- - - 72 > 34.2 Helms (1967)
Rainbow trout 12 6.5-9.5 46-48 96 565-1020 McKim et al. (1976)
(green egg)
Rainbow trout 12 6.5-9.5 - 96 198-435 McKim et al. (1976)
(eyed egg)
Rainbow trout 12 6.5-9.5 - 96 89.5-112 Brungs et al. (1978)
(sac larvae)
Rainbow trout 12 6.5-9.5 - 96 61.9-106 Brungs et al. (1978)
(fingerling)
Rainbow trout 12 6.5 8 3 492a Bills et al. (1977)
(fingerling) 12 6.5 8 6 262a Bills et al. (1977)
12 6.5 8 24 120a Bills et al. (1977)
12 6.5 8 96 47.2a Bills et al. (1977)
Rainbow trout 12 - 20 96 118 Brungs et al. (1978)
--------------------------------------------------------------------------------------------------------
Table 24 (contd).
--------------------------------------------------------------------------------------------------------
Fish (contd).
Rainbow trout 12 7.5 40-48 24 214-7200 McKim et al. (1976)
Rainbow trout 12 7.5-8.2 30-245 96 440-618 McKim et al. (1976)
Rainbow trout - - - 48 59.2 Schneider (1979)
- - - 24 76.6 Willford (1966)
- - - 48 62.2 Willford (1966)
Brown trout - - - 24 120.3 Willford (1966)
- - - 48 68.5 Willford (1966)
Brook trout - - - 24 72.5 Willford (1966)
- - - 48 58.1 Willford (1966)
Lake trout - - - 24 81.4 Willford (1966)
(fingerling) - - - 48 61.8 Willford (1966)
12 6.5 8 6 241a Bills et al. (1977)
12 6.5 8 24 56.4a Bills et al. (1977)
12 6.5 8 96 40.0a Bills et al. (1977)
Bluegill sunfish - - - 24 68.5 Willford (1966)
(fingerling) - - - 48 51.8 Willford (1966)
- - - 72 30.4 Helms (1967)
12 6.5 8 3 916a Bills et al. (1977)
12 6.5 8 6 640a Bills et al. (1977)
12 6.5 8 24 84.4a Bills et al. (1977)
12 6.5 8 96 40.0a Bills et al. (1977)
- - - 24 53.7 Schneider (1979)
- - - 48 34.0 Schneider (1979)
- - - 96 25.2 Schneider (1979)
Largemouth bass - - - 72 38 Helms (1967)
(fingerling) 12 6.5 8 6 412a Bills et al. (1977)
12 6.5 8 24 113a Bills et al. (1977)
12 6.5 8 96 57.2a Bills et al. (1977)
--------------------------------------------------------------------------------------------------------
Table 24 (contd).
--------------------------------------------------------------------------------------------------------
Organism/species Temperature pH Hardness Duration (LC50) Reference
( °C) degree of ex- (mg/litre)
posure (h)
--------------------------------------------------------------------------------------------------------
Fish (contd).
Smallmouth bass 12 6.5 8 24 88.8a Bills et al. (1977)
(fingerling) 12 6.5 8 96 54.4a Bills et al. (1977)
Striped bass - - - 24 31.8 Wellborn (1969)
- - - 48 11.8 Wellborn (1969)
- - - 96 6.7 Wellborn (1966)
Channel catfish - - - 24 50.7 Willford (1966)
- - - 48 35.5 Willford (1966)
- - - 96 25.5b Clemens & Sneed
(1958, 1959)
(fingerling) 12 6.5 8 3 198a Bills et al. (1977)
12 6.5 8 6 92.8a Bills et al. (1977)
12 6.5 8 24 48.8a Bills et al. (1977)
12 6.5 8 96 26.3a Bills et al. (1977)
Black bullhead - - - 72 17.1 Helms (1967)
(fingerling) 12 6.5 8 24 69.2a Bills et al. (1977)
12 6.5 8 96 24.8a Bills et al. (1977)
Golden shiner 72 23.6 Helms (1967)
American eel 31.1 Hinton & Eversole
glass stage - - - 96 (1978, 1979, 1980)
black stage - - - 96 83.1 Hinton & Eversole
(1978, 1979, 1980)
yellow stage - - - 96 122.1 Hinton & Eversole
(1978, 1979, 1980)
--------------------------------------------------------------------------------------------------------
Table 24 (contd).
--------------------------------------------------------------------------------------------------------
Fish (contd).
Carp - - - 72 > 26.6 Helms (1967)
- - - 2 74a Suzuki & Kimara (1977)
Zebrafish - - - 96 41 Wellens (1982)
Golden orfe - - - 48 22 Wellens (1982)
- - - 48 32.4b Juhnke & Luedemann
- - - 48 15.0b (1978)
Harlequin fish - - - 24 76 Alabaster (1969)
- - - 48 50 Alabaster (1969)
Tilapia - - - 72 > 38.0 Helms (1967)
--------------------------------------------------------------------------------------------------------
a Flow through bioassay.
b Method not stated.
Table 25. Toxicity of formalin (37% formaldehyde) for selected aquatic
invertebrates in soft water at 16 °Ca
------------------------------------------------------------------------------------------------------
Species LC50 and 95% confidence interval (µlitre/litre) at
1 h 3 h 6 h 24 h 96 h
------------------------------------------------------------------------------------------------------
Seed shrimp (ostracods)b 9.00 6.40 1.20 1.15 1.05
Cypridopsis sp. 6.83-11.9 4.91-8.34 0.664-2.17 0.690-1.97 0.590-1.87
Freshwater prawnb - 2150 1900 1105 465
Palawmonetes kadiakensis - 1948-2373 1588-2273 896-1362 368-588
Bivalvesc 800 126
Corbicula sp. - - - 638-1003 80.9-196
Snaild 3525 1340 780 710 93.0
Helisoma sp. 3201-3881 953-1883 629-967 544-925 69.5-124
Backswimmerd - - - 4500 835
Notonecta sp. 3006-6735 652-1069
------------------------------------------------------------------------------------------------------
a From: Bills et al. (1977).
b Toxicity based on immobility.
c Toxicity based on ability to resist attempts to open valves and respond to tactile stimulus.
d Toxicity based on ability to respond to tactile stimulus.
Nematodes in peat were killed by application of 370 g formal-
dehyde/litre solution at 179 ml/m3 (Lockhart, 1972).
Changes in populations of the cereal cyst nematode Heterodera
avenae and in crop growth in a sandy loam soil were studied in 1974-78
(Kerry et al. 1982). Fungal parasites attack H. avenae females and eggs
resulting in poor multiplication of the nematode. The number of cysts
containing nematode eggs, after harvest, was not affected by formalin
(380 g formaldehyde/litre) applied as a drench at 3000 litre/ha in
1977. However, fecundity doubled in treated soil, and nematode multi-
plication increased 18.6 times compared with 3.8 times in untreated
plots. When the plots were irrigated in 1978, the numbers of cysts and
fecundity increased in formalin-treated soils, resulting in a 0.3- to
14.6-fold increase due to suppression of fungal parasites.
The yellow rice borer ( Tryporyza incertulas ) ( Lepidoptera ) is one
of the most serious pests of rice. To obtain sterile males, it has to
be mass-reared on an artificial diet containing formaldehyde (Wang et
al., 1983); the same has been reported for the pink borer ( Sesamia
inferens ) (Siddiqui et al., 1983).
In ruminants, deamination of dietary proteins by rumen micro-
organisms is of importance, because of loss of essential nitrogen from
the rumen as ammonia. Formaldehyde protects dietary-protein from
microbial proteolysis in the rumen by reacting with free amino groups
in the protein, forming inter- and intramolecular methylene bridges
(Siddons et al., 1982). Thus, there is an increase in the efficiency
of utilization of amino acids for wool (10 g formaldehyde/kg protein)
and body growth in sheep and other ruminants (Faichney, 1970; Ferguson,
1970; Hemsley et al., 1973). Differences in nitrogen retention were
found, but no significant differences in wool growth or live-weight
gain, when sheep were fed formaldehyde-treated linseed meal and
meatmeal (2.5% formalin) (Rattray & Joyce, 1970). Mills et al. (1972)
showed that 14C-formaldehyde bound to a sodium caseinate-oil mixture
was rapidly metabolized by sheep and goat tissues and eliminated via
expired air, urine, and faeces, but was not accumulated in the milk or
in the carcass. To study the digestion in the small intestine of young
bulls of the protein of rapeseed meal, treated or not treated with
formaldehyde, Kowalczyk et al. (1982) fitted each bull with cannulae in
the rumen and abomasum. Formaldehyde-treated rapeseed meal was poorly
digested. The nutritional value of soybean meal that had been treated
with 3 g formaldehyde/kg was investigated by Crooker et al. (1983).
Analysis of covariance revealed that the digestibility of dietary crude
protein by cows fed formaldehyde-treated meal was lower than that in
the controls (62.4% versus 65.4%) as was the milk-protein content.
Erfle et al. (1986) fed lactating cows with formaldehyde-treated
soybean meal and found that milk-protein levels were significantly
decreased. After treatment with formaldehyde, lysine and tyrosine were
lost from the soybean meal.
Grenet (1983) studied the utilization of grass-silage nitrogen in
growing sheep and found that formic acid had a beneficial effect
(decreased urinary-nitrogen loss). However, the addition of 1.5 litre
formalin/tonne of green forage did not improve nitrogen-retention;
higher quantities of formaldehyde tended to have an unfavourable
effect, particularly with lucerne silage.
7.4 Plants
A study was carried out by Sangines et al. (1984) to examine the
protective effects of formaldehyde on ensilaged whole peanut plant
protein. Formaldehyde (50, 100, 150, and 200 g/litre) was added at the
rate of 5 litres/tonne. A control without any formaldehyde was
included. There were no significant differences in pH among treatments
(5.56-5.70). The ammonia concentration dropped significantly in all
treatments, a finding that suggests a protective effect against
protein-nitrogen degradation to non-protein nitrogen (NH3). Lactic
acid fermentation was observed, without any difference between treated
and control silage. Nevertheless, there was a reduction in the
propionic acid and ethanol concentrations in all the silages. It was
concluded that there was an inhibition of the fermentation process in
all the silages treated, and that the addition of formaldehyde at the
5% level is a satisfactory way of protecting this type of feed.
In agriculture, urea-formaldehyde fertilizers are used to improve
crops. At concentrations of up to 0.3 g/kg soddy podsolic soil,
formaldehyde did not change the nitrogen and carbohydrate metabolism in
barley plants (Lebedeva et al., 1985). However, increased doses of the
fertilizer caused negative effects on the biological properties of the
soil (Rakhmatulina et al., 1984).
Doman et al. (1961) studied the conversion of gaseous formaldehyde
absorbed by leaves of kidney beans and barley plants from the atmos-
phere, using 14C tracing. The activity appeared first in phosphate
ester fractions and later in the amino acids alanine, serine, aspartic
acid and unidentified products, especially when the experiments were
conducted in the dark. Zemlianukhin et al. (1972), also using 14C
tracing, studied the metabolism in 12-day-old maize seedlings, of
formic acid, which was oxidized to carbon dioxide or metabolized to
cellular constituents.
Pollen germination has been shown to be sensitive to various air
pollutants. Masaru et al. (1976) sowed lily pollen grains ( Lilium
longiflorum ) on culture medium. After being exposed to formaldehyde in
a fumigation chamber, for 24 h, pollen tube length was measured. A 5-h
exposure to formaldehyde at 0.44 mg/m3 (0.37 ppm) resulted in a sig-
nificant reduction in pollen-tube length, whereas a 1- or 2-h exposure
was innocuous. When the formaldehyde concentration was increased to
2.88 mg/m3 (2.4 ppm), a 1-h exposure caused a decrease in tube length.
The investigators observed that, with respect to pollen, the activity
of formaldehyde was comparable with that of nitrogen dioxide. To test
combinations of pollutants, pollen grains were exposed to sulfur
dioxide at 1.79 mg/m3 (0.69 ppm) for 30 min or to nitrogen dioxide at
0.28 mg/m3 (0.15 ppm) for 30 or 60 min. This treatment led to slight
inhibition of tube elongation. A second exposure to formaldehyde at
0.3 mg/m3 (0.26 ppm) led to significant inhibition of pollen tube
length (about 30-40% of the length of control pollen-tubes).
A sealed Plexiglas chamber with temperature and humidity control
and illuminated externally with wide spectrum grow lights was used to
evaluate the ability of golden pothos ( Scindapsus aureus ), nephthytis
( Syngonium podophyllum ), and the spider plant ( Chlorophytum elatum
var. vittatum ) to remove formaldehyde from contaminated air at initial
concentrations of 18-44 mg/m3. Under the conditions of this study,
the spider plant proved most efficient by sorbing and/or removing up to
2.27 µg formaldehyde/cm2 leaf surface area in a 6-h exposure
(Wolverton et al., 1984).
Various factors influence the response of a plant receptor to
formaldehyde exposure. These include genetic factors, stage of plant
development, age of tissue, climatic factors, such as temperature,
relative humidity, light quality, light intensity, photoperiod, rate of
air movement, and soil factors, such as moisture, aeration, and nutri-
ents. Most studies dealing with the influence of formaldehyde exposure
on plants suffer from lack of such information.
8. EFFECTS ON EXPERIMENTAL ANIMALS AND IN VITRO TEST SYSTEMS
Concern about the toxicological effects of formaldehyde is related
to effects resulting from single or repeated exposures including irri-
tation, cytotoxicity, cell proliferation, and sensitization, and
effects resulting from long-term exposures, particularly cancer.
The most significant properties of formaldehyde are its potential
to cause irritation and, at high concentrations after long-term
exposure, nasal tumours in rats and statistically not significant nasal
tumours in mice.
8.1 Skin and Eye Irritation, Sensitization
Formaldehyde is known to be a primary skin and eye irritant, the
local tissue reaction increasing with increased dose. However, this is
based on anecdotal evidence rather than animal studies. The only report
is that of Carpenter & Smyth (1946) who found formaldehyde to be an eye
irritant for rabbits.
The sensitizing potential of aqueous formaldehyde was evaluated
with the guinea-pig maximization test (GPMT) in two laboratories
(Copenhagen and Stockholm) using different guinea-pig strains
(Andersen et al., 1985). Six intradermal (0.1-30 g/litre) and 6 topical
(5-200 g/litre) concentrations were used for induction, and formal-
dehyde at 10 and 1 g/litre was used for challenge. The incidence of
contact sensitivity depended on the intradermal, but not on the
topical, induction dose. Statistical analyses showed a non-linear
dose-response relationship. The estimated maximal sensitization rate
in Copenhagen was 80% after intradermal induction with 0.65% formal-
dehyde; in Stockholm, it was 84% after induction with 0.34%. The data
from the two laboratories gave parallel displaced dose-response curves,
suggesting that the guinea-pig strain used in Stockholm was signifi-
cantly more susceptible to formaldehyde than the strain used in
Copenhagen. The EC50 (formaldehyde concentration at which 50% of the
guinea-pigs were sensitized at 72 h) at a 10 g/litre challenge concen-
tration was 0.6 g/litre in Copenhagen and 0.24 g/litre in Stockholm.
Other studies are summarized in Table 26. The results show that
aqueous formaldehyde solution is a sensitizer for the skin.
Lee et al. (1984) exposed guinea-pigs to formaldehyde at 7.2 mg/m3
or 12 mg/m3, for 6 or 8 h/day, on 5 consecutive days. The animals
were evaluated for skin sensitivity (production of anti-formaldehyde
antibody) and respiratory sensitivity (both immediate and delayed-
onset) to formaldehyde, which was shown to be a skin sensitizer without
causing detectable pulmonary hypersensitivity.
8.2 Single Exposures
Acute toxicity has been studied in several animal species (Table
27).
Table 26. Contact allergy predictive tests in guinea-pigs
----------------------------------------------------------------------------
Induction Challenge Sensitization Test Reference
dose (%) dose (%) (number positive/
number tested)
----------------------------------------------------------------------------
30 1 2/7 open epicutaneous Maibach (1983)
10 1 5/8
3 1 3/8
1 1 2/6
0.3 1 2/6
0.1 1 0/6
5 5 7/20 epicutaneous Guillot & Gonnet
maximization (1985)
10 5 3/10 cumulative contact Tsuchiya et al.
5 5 2/10 enhancement test (1985)
1 5 0/10
0.2 5 0/10
10 1 4/10 Tsuchiya et al.
5 1 2/10 (1985)
1 1 0/10
0.2 1 0/10
10 0.2 1/10 Tsuchiya et al.
5 0.2 0/10 (1985)
1 0.2 0/0
0.2 0.2 0/0
-----------------------------------------------------------------------------
Table 27. Acute toxic effects of formaldehyde on laboratory animals
--------------------------------------------------------------------------------------------------------
Species Route Dose (duration) Effect/response Reference
--------------------------------------------------------------------------------------------------------
Rat oral 800 mg/kg body weight LD50 Smyth et al. (1941); Tsuchiya
et al. (1975)
subcutaneous 420 mg/kg body weight LD50 Skog (1950)
intravenous 87 mg/kg body weight LD50 Langecker (1954)
inhalation 984 mg/m3 (30 min) LC50 Skog (1950)
inhalation 578 mg/m3 (4 h) LC50 Nagorny et al. (1979)
Mouse subcutaneous 300 mg/kg body weight LD50 Skog (1950)
inhalation 497 mg/m3 (4 h) LC50 Nagorny et al. (1979)
Rabbit dermal 270 mg/kg body weight LD50 Lewis & Tatken (1980)
dermal 0.1-20% skin irritation: NRC (1981)
mild to moderate
eye 0.5 ml eye irritation: Carpenter & Smyth (1946)
grade 8 on a
scale of 10
Guinea- oral 260 mg/kg body weight LD50 Smyth et al. (1941)
pig
dermal 0.1-20% skin irritation: Colburn (1980)
mild to moderate
dermal 1% (open application) sensitization: US CPSC (1978)
positive
3% (open application) sensitization: US CPSC (1978)
positive
1% (intradermal) sensitization: Colburn (1980)
positive
--------------------------------------------------------------------------------------------------------
The odour and irritant properties of formaldehyde serve as repel-
lents. Kane & Alarie (1977) used the decrease in respiratory rate of
mice as an index of irritation. At 0.6 mg formaldehyde/m3 air, an
irritant effect on the eyes, nose, and throat occurred, and tolerance
to the irritant effects of formaldehyde did not develop.
Exposure to high concentrations of formaldehyde vapour (> 120
mg/m3) caused hypersalivation, acute dyspnoea, vomiting, muscular
spasms, and can finally lead to the death of test animals (Skog, 1950;
Horton et al., 1963; Bitron & Aharonson, 1978).
8.3 Short-term Exposures
8.3.1 Inhalation studies
Inhalation studies are summarized in Table 28.
A range finding study was conducted in which rats and mice were
exposed to atmospheres containing 4.8, 15, or 46 mg formaldehyde/m3
(4, 12.7, or 40 ppm). Exposures were for approximately 6 h/day, 5
days/week, for 13 weeks, except for the high dose level, which was
terminated after 2 weeks (Mitchell et al., 1979). Exposure of both
mice and rats to concentrations of inhaled formaldehyde of 46 mg/m3
(40 ppm) resulted in ulceration or necrosis of the nasal turbinate
mucosa in a significant number of animals of each species. Both sexes
of rats had a high incidence of tracheal mucosal ulceration and
necrosis, whereas only a few male mice exhibited this lesion. Pulmon-
ary congestion was prominent in both male and female rats and in male
mice at the highest dose level. Female mice of both the control and
high-dose group had a similar incidence of pulmonary congestion. Sec-
ondary lesions encountered in rats exposed to this dose of formaldehyde
seemed to be related to bacterial septicaemia due to a damaged respir-
atory mucosa.
Groups of 10 male and 10 female B6C3F1 mice were exposed to 2.4,
4.8, 12, 24, or 48 mg formaldehyde vapour/m3 (2, 4, 10, 20, or 40 ppm)
for 6 h/day, 5 days/week, over 13 weeks (Maronpot et al., 1986).
Clinical abnormalities (dyspnoea, listlessness, and hunched posture),
significant mortality, and body weight loss were observed in the
48 mg/m3 groups. Pathological changes were observed in the nose,
larynx, trachea, and bronchi of treated males and females, and in the
uterus and ovaries of treated females. Squamous metaplasia and inflam-
mation were present in the nasal tissues of both male and female mice
in the 12-48 mg/m3 (10, 20, 40 ppm) groups and in the larynx of both
males and females in the 24 and 48 mg/m3 (20, 40 ppm) groups. In some
mice, epithelial-lined, irregular connective tissue bands spanned the
tracheal lumen. Metaplasia of the bronchial epithelium was confined to
the groups exposed to 48 mg/m3. The effects on the respiratory system
were more prevalent in male than in female mice. Hypoplasia of the
uterus and ovaries, probably secondary to body weight loss, was con-
fined to the 48 mg/m3 (40 ppm) exposure group.
Table 28. Short-term formaldehyde inhalation studies
--------------------------------------------------------------------------------------------------------
Species Exposure Concentration Effect Reference
mg/m3 (ppm)
--------------------------------------------------------------------------------------------------------
Nose-only inhalation
Rat 6 h/day, 5 days/week, 3.6 (3) no adverse findings AIHA
for 4 weeks (1983)
6 h/day, 5 days/week, 19, 73, (16, 61, antibody inhibition AIHA
for 4 weeks 120 99) (1983)
Inhalation
Rat 8 h/day (continuous), 6, 12 (5, 10) slightly increased prolifer- Wilmer
5 days/week, for (equivalent to ation of nasal epithelium; et al.
4 weeks 40 ppm x h or slight hypermetaplasia of (1987)
80 ppm x h) nasal epithelium
8.5 h/day (interrupted), 12, 24 (10, 20) strongly increased prolifer- Wilmer
5 days/week, for (equivalent to ation of nasal epithelium; et al.
4 weeks 40 ppm x h or moderate hypermetaplasia of (1987)
80 ppm x h) nasal epithelium
Rat 22 h/day, for 90 days 1.9 (1.6) no adverse findings Dubreuil
et al.
(1976)
22 h/day, for 45 days 5.4 (4.55) decreased weight gain Dubreuil
et al.
(1976)
22 h/day, for 60 days 9.6 (8.07) decreased liver weight; Dubreuil
eye irritation et al.
(1976)
6 h/day, 5 days/week, 4.8 (4) no adverse effect Mitchell
for 13 weeks et al.
(1979)
--------------------------------------------------------------------------------------------------------
Table 28 (contd).
--------------------------------------------------------------------------------------------------------
Inhalation (contd).
Rat 6 h/day, 5 days/week, 15 (12.7) nasal erosion Mitchell
for 13 weeks et al.
(1979)
6 h/day, 5 days/week, 48 (40) nasal ulceration Mitchell
for 2 weeks et al.
(1979)
8 h/day (continuous), 1.2 (equivalent no adverse effects Wilmer
5 days/week, for 9.6 to 8 ppm x h) et al.
13 weeks (1986)
8.5 h/day (intervals), 2.4 (equivalent no adverse effects Wilmer
5 days/week, for 9.6 to 8 ppm x h) et al.
13 weeks (1986)
8 h/day, 5 days/week, 2.4 (equivalent no adverse effects Wilmer
for 13 weeks 19.2 to 16 ppm x h) et al.
(1986)
8.5 h/day, 5 days/week, 4.8 (equivalent hyper- and metaplasia of Wilmer
for 13 weeks 19.2 to 16 ppm x h) nasal respiratory epithelium et al.
(1986)
6 h/day, 5 days/week, 0.36 (0.3) transient, slight increase Zwart
for 13 weeks in cell turnover rate of the et al.
nasal respiratory epithelium (1987)
6 h/day, 5 days/week, 1.2 (1) transient, slight increase Zwart
for 13 weeks in cell turnover rate of et al.
the nasal respiratory (1987)
epithelium
6 h/day, 5 days/week, 3.6 (3) 5- to 10-fold increase in Zwart
for 13 weeks cell turnover rate and et al.
squamous metaplasia of the (1987)
nasal respiratory epithelium
---------------------------------------------------------------------------------------------------------
Table 28 (contd).
---------------------------------------------------------------------------------------------------------
Species Exposure Concentration Effect Reference
mg/m3 (ppm)
---------------------------------------------------------------------------------------------------------
Inhalation (contd).
Rat 6 h/day, 5 days/week, 1.2 (1) questionable hypermetaplasia Woutersen
for 13 weeks of the nasal respiratory et al.
epithelium (1987)
6 h/day, 5 days/week, 12 (10) squamous metaplasia of nasal Woutersen
for 13 weeks respiratory epithelium et al.
(1987)
6 h/day, 5 days/week, 24 (20) transient excitation and Woutersen
for 13 weeks uncoordinated locomotion; et al.
growth retardation; de- (1987)
creased level of plasma-
protein; increased activity
of several plasma enzymes;
squamous metaplasia of the
nasal respiratory and olfac-
tory epithelium; squamous
metaplasia of laryngeal
epithelium
6 h/day, 5 days/week, 2.4-48 (2-40) 12-48 mg/m3: histological Maronpot
for 13 weeks lesions in the upper respira- et al.
tory system; 48 mg/m3: death (1986)
22 h/day, 7 days/week, 1.2 (1) no adverse findings Rusch et
for 26 weeks al. (1983)
22 h/day, 7 days/week, 3.6 (3) squamous metaplasia; depres- Rusch et
for 26 weeks sion in body weight gain al. (1983)
---------------------------------------------------------------------------------------------------------
Table 28 (contd).
---------------------------------------------------------------------------------------------------------
Inhalation (contd).
Mouse 6 h/day, 5 days/week, 4.8 (4) no adverse findings Mitchell
for 13 weeks et al.
(1979)
6 h/day, 5 days/week, 15 (12.7) no adverse findings
for 13 weeks
6 h/day, 5 days/week, 48 (40) nasal ulceration in males
for 2 weeks
Hamster 22 h/day, 7 days/week, 1.2 and (1 and no adverse findings Rusch et
for 26 weeks 3.6 3) al. (1983)
Guinea-pig 6 h/day, 5 days/week, 1.2 (1) hyperkeratosis in the cavity Marshall
for 8 weeks (reversible after 30 days); (1983)
mucus flow elevated; foci of
squamous metaplasia of res-
piratory epithelium
Monkey 22 h/day, 7 days/week, 1.2 (1) metaplasia in nasal turbin- Rusch et
(cynomolgus) for 26 weeks ates in 1/6 exposed al. (1983)
22 h/day, 7 days/week, 3.6 (3) metaplasia in nasal turbin- Rusch et
for 26 weeks ates in 6/6 exposed al. (1983)
Monkey 6 h/day, 5 days/week, 7.2 (6) mild degeneration and early Monticello
(rhesus) for 1 or 6 weeks squamous metaplasia of nasal et al.
passages, trachea and bronchi (1989)
in 6/6 exposed. Percentage of
nasal surface area affected
was greater in 6-week exposure
group
---------------------------------------------------------------------------------------------------------
Groups of 6 male cynomolgus monkeys, 20 male and 20 female Fischer
344 rats, and 10 male and 10 female Syrian golden hamsters were exposed
to 0, 0.24, 1.2, or 3.7 mg/m3 (0, 0.2, 1, or 3 ppm) formaldehyde
vapour (98.8% pure) for 22 h/day, 7 days/week, over 26 weeks. Squamous
metaplasia of the nasal turbinates was evident in 6/6 monkeys exposed
to 3.7 mg/m3 (3 ppm) and in 1/6 exposed to 1.2 mg/m3 (1 ppm).
Squamous metaplasia and basal cell hyperplasia of the respiratory
epithelium of the nasal cavity were significantly increased in rats
exposed to 3.7 mg/m3 (3 ppm). The same group exhibited marked
depressions in body weight gain. No exposure-related effects were
demonstrated in hamsters (Rusch et al., 1983).
Two groups of 3 adult (aged 4-5 years) male rhesus monkeys were
exposed to 7.2 mg/m3 (6 ppm) formaldehyde in inhalation chambers. One
group was exposed 6 h/day for 5 days; the other group was exposed for
6 h/day, 5 days/week for 6 weeks. A control group of 3 monkeys was sham
exposed to filtered room air for 6 h/day, 5 days/week for 6 weeks. Both
exposed groups showed mild degeneration and early squamous metaplasia
in parts of the transitional and respiratory epithelium of the nasal
passages and respiratory epithelium of the trachea and major bronchi.
The nasal surface area involved was significantly increased in the
6 week exposure group. Cell proliferation rates were significantly
increased and remained elevated 6 weeks after the termination of
exposure (Monticello et al., 1989).
Fifteen-week-old male Hartley guinea-pigs were exposed for 6 h/day,
5 days/week, for 8 weeks, to 0.12, 1.2, or 12 mg formaldehyde/m3
(Marshall et al., 1983). Animals were sacrificed at 1 and 30 days
after the end of exposure, and tissue samples were taken to study the
histology and lung biochemistry. Body weight, nasal mucous clearance
velocity, and airway sensitivity to inhaled histamine were measured
after 2, 4, and 8 weeks of exposure and 2 and 4 weeks after completion
of exposure. Nasal mucous clearance velocity increased by 25% after 4
weeks of exposure to 12 mg/m3, but returned to control values 2 weeks
after the end of exposure. Dose-related histological findings included
hyperkeratosis and squamous metaplasia of the respiratory epithelium
occurring in foci in the anterior half of the nasal cavities. Thirty
days after exposure, squamous metaplasia had resolved; however, slight
hyperkeratosis of respiratory epithelium was still present in guinea-
pigs exposed to 12 mg formaldehyde/m3. Altered airway sensitization
to inhaled histamine was not noted in exposed guinea-pigs. No differ-
ences were observed in body weights and lung biochemical end-points
between control and exposed guinea-pigs.
The acute effects of inhaled formaldehyde on the nasal mucociliary
apparatus of male F-344 rats were studied by Morgan et al. (1986)
using whole-body exposures. Formaldehyde exposures ranged from a
single 6-h period up to repeated 6-h exposures daily for 3 weeks, with
exposure concentrations of 18, 7.2, 2.4, or 0.6 mg/m3. Within 1 h
of the last exposure, the rats were killed and the nasal passages
examined for effects on nasal mucociliary function. Exposure to
18 mg formaldehyde/m3 induced inhibition of mucociliary function in
specific regions of the nose, and mucostasis was generally more exten-
sive than ciliastasis. These effects, which were initially confined to
the anterior regions of the nose, became progressively more extensive
for up to 2 weeks of exposure with only very slight progression during
the third week. Inhibition of mucociliary function was much less
severe with exposure to 7.2 mg/m3, minimal at 2.4 mg/m3, and not
detected in rats following exposure to 0.6 mg/m3.
Woutersen et al. (1987) exposed male and female rats to 0, 1.2, 12,
or 24 mg formaldehyde/m3 for 6 h/day, 5 days/week, over 13 weeks;
definite adverse effects were observed at 12 and 24 mg/m3, but the
study was inconclusive with respect to whether 1.2 mg/m3 was a cyto-
toxic effect level for the nasal epithelium.
The possibility of the hepatotoxicity of formaldehyde for rats was
investigated by Woutersen et al. (1987). It was concluded that formal-
dehyde was not hepatotoxic at concentrations as high as 12 mg/m3
(10 ppm). At 24 mg/m3 (20 ppm), there was a slight increase in the
levels of certain plasma-enzymes suggesting a hepatotoxic effect, how-
ever, histopathological examinations did not reveal any liver damage,
and there were no changes in liver weight or liver-glutathione concen-
trations. The slight increase in plasma-enzyme levels may have been
caused by growth retardation (Woutersen et al., 1987).
Zwart et al. (1987) exposed rats (50 per sex and group) to 0, 0.36,
1.2, or 3.6 mg formaldehyde/m3 for 6 h/day, 5 days/week, over 13
weeks. Definite adverse effects on the nasal epithelium were observed
at 3.6 mg/m3. The authors concluded there was some indication that
formaldehyde at levels of 0.36 and 1.2 mg/m3 challenged the nasal
mucociliary and regenerative defence systems at the beginning, but not
at the end, of the study.
In a 13-week inhalation study, male rats were exposed for 5 days
per week to 0, 1.2, or 2.4 mg formaldehyde/m3, continuously (8 h per
day), or to 2.4 or 4.8 mg formaldehyde/m3 intermittently (8 successive
1-h periods a day, each consisting of 30 min of exposure and 30 min of
non-exposure) (Wilmer et al., 1986). The only adverse effect (hyper-
metaplasia of the nasal respiratory epithelium) was found in animals
exposed to 4.8 mg/m3. This study showed that the concentration is
more important than the total dose for the cytotoxic effects of formal-
dehyde on the nose.
A 4-week inhalation study on male rats was carried out by Wilmer et
al. (1987) in which the animals were exposed for 5 days/week to 0, 6,
or 12 mg formaldehyde/m3, continuously for 8 h/day, or 12 or 24 mg
formaldehyde/m3 intermittently (8 successive 1-h periods per day, each
consisting of 30 min of exposure and 30 min of non-exposure). This
study also showed that the concentration rather than the total dose of
formaldehyde determined the severity of the cytotoxic effects on the
nasal epithelium.
Fifteen male rats were exposed to vapourizing 10% formalin solution
(3.7% formaldehyde) by inhalation for 2-22 weeks; their tracheas were
removed and examined microscopically after various periods of exposure;
a wide spectrum of morphological changes in the epithelium and under-
lying connective tissues was observed. In addition to chronic inflam-
mation, metaplastic changes, including squamous metaplasia and
dysplasia of the epithelium, were induced by formaldehyde (Al-Abbas et
al., 1986).
The immunotoxicity of formaldehyde was studied in mice by Dean et
al. (1984). Female B6C3F1 mice underwent inhalation exposure to
18 mg/m3 for 6 h/day, 5 days/week, over 3 weeks. Most immune functions
involving T and B lymphocytes and macrophages were not impaired and
there was an enhanced resistance to Listeria monocytogenes . In a
later study by the same group (Adams et al., 1987), exposure of mice to
18 mg formaldehyde/m3 (15 ppm) for 6 h daily over 3 weeks caused an
increased (approximately two-fold) competence for release of hydrogen
peroxide (H2O2) from the peritoneal macrophages. Enhanced function
of the macrophages may be responsible for the enhanced lost resistance
reported by Dean et al. (1984).
8.3.2 Oral studies
In a 4-week, drinking-water study on rats, using formaldehyde
levels of 0, 5, 25, or 125 mg/kg body weight per day, adverse effects
attributable to formaldehyde were encountered in the high-dose group
only, and comprised decreased plasma-protein levels and hyperkeratosis
and gastritis in the fore- and glandular stomach, respectively (Til et
al., 1987).
Administration of formaldehyde in the drinking-water to Sprague-
Dawley rats at a dose of 150 mg/kg body weight per day and in the diet
to beagle dogs at a dose of 100 mg/kg body weight per day for a period
of 13 weeks was found to result in a slightly depressed growth rate; no
effects on the stomach were observed (Johannsen et al., 1986).
During an 18-day study, rats were fed a diet of soybean meal
treated with formaldehyde (Schmidt et al., 1973). The use of more than
2 ml formalin (40%)/100 g soybean protein reduced growth, and also
nitrogen retention in nitrogen balance studies.
8.4 Long-Term Exposure and Carcinogenicity
8.4.1 Inhalation
Exposure of B6C3F1 mice and Fischer 344 rats to 2.4, 7.2, or
18 mg formaldehyde vapour/m3 (2, 6, or 15 ppm) for up to 24 months
resulted in chronic toxicity. The survival of mice did not appear to
be related to the concentration of formaldehyde to which they were
exposed; however, exposure to a level of 17.6 mg/m3 resulted in
reduced body weight. Several lesions were seen in the nasal cavities
of mice exposed to concentrations of 7.2 or 18 mg/m3 (6 or 15 ppm),
including dysplasia and squamous metaplasia of the respiratory epi-
thelium, purulent or seropurulent rhinitis, and atrophy of the olfac-
tory epithelium. Three months after exposure was discontinued
(27 months), the nasal lesions had regressed. In the rats, several
lesions occurred in the nasal cavities at the low concentration of
2.4 mg/m3 (2 ppm); these increased in extent and severity with
increasing concentrations. The lesions included dysplasia and squamous
metaplasia of the respiratory epithelium, goblet-cell hyperplasia, and
purulent or seropurulent rhinitis. Rats exposed to 18 mg/m3 (15 ppm)
also exhibited goblet-cell metaplasia of the olfactory epithelium,
respiratory epithelial hyperplasia, squamous epithelial hyperplasia,
squamous atypia, and papillary hyperplasia; dysplasia and squamous
metaplasia of the tracheal epithelium were also detected. The incidence
of squamous metaplasia in rats exposed to 2.4 or 6.7 mg/m3 (2 or
5.6 ppm) regressed within 3 months of the termination of exposure
(Swenberg et al. 1980; Kerns et al., 1983) (see Table 30). Male Syrian
golden hamsters exposed to diethylnitrosamine by sc injection (0.5 mg,
once per week, for 10 weeks) and to formaldehyde (36 mg/m3 via inha-
lation, 48 h/week prior to each injection, and subsequently continued
for the life-time of each animal) developed tracheal carcinomas
(Dalbey, 1982). Male Syrian golden hamsters exposed to up to 12 mg
formaldehyde/m3 (10 ppm) for 5 h/day and 5 days per week for their
life-time did not show any tumours but 5% showed hyperplastic and meta-
plastic areas on the nasal epithelium. The author concluded that
formaldehyde may act as a cofactor in carcinogenesis in the trachea.
Following exposure of Sprague-Dawley rats to formaldehyde
17 mg/m3 (14 ppm) alone, or in combination (pre-mixed or non-pre-
mixed) with HCl 14 mg/m3 (10 ppm), for 6 h/day, 5 days/week, for life
(Table 29), rhinitis, hyperplasia, and squamous metaplasia in lar-
yngeal-tracheal segments and nasal mucosa were observed (Albert et al.,
1982; Sellakumar et al., 1985).
Albert et al. (1982) exposed rats to a mixture of gaseous formal-
dehyde (17.9 mg/m3) and hydrogen chloride (16.9 mg/m3) for 6 h/day,
5 days/week, for life. In the exposure chamber, a bis-chloromethyl-
ether (BCME) concentration of 0.5-2 µg/m3, due to the chemical
reaction of formaldehyde and hydrogen chloride, was estimated.
Sellakumar et al. (1985) calculated levels of BCME under similar con-
ditions of 0.5-2.05 µg/m3 (0.1-0.4 ppb). Nasal squamous cell carci-
nomas were found in 25/99 rats and papillomas in 3/99 rats; squamous
metaplasia of the nasal epithelium was found in 64/99 of the exposed
rats.
A subsequent report (Sellakumar et al., 1985) of studies on
combined exposure to hydrogen chloride and formaldehyde showed that the
carcinogenic response to formaldehyde does not result from the BCME
formed by the mixture of the gases.
Tobe et al. (1985) exposed male F-344 rats for 6 h/day, 5
days/week, over 28 months, to 0.36, 2.4, or 17 mg formaldehyde/m3.
Rhinitis accompanied by desquamation was found in all groups. In all
formaldehyde-exposed groups, nasal epithelial hyperplasia and squamous
metaplasia with hyperplasia were seen. In the 17 mg/m3 group,
squamous cell carcinoma was recognized in 14 rats and papilloma in 5 of
32 rats exposed.
Table 29. Summary of carcinogenicity studies of formaldehyde on animals
---------------------------------------------------------------------------------------------------------
Species/ Number of Route of Dosage Findings Reference
Strain animals exposure
(sex)
---------------------------------------------------------------------------------------------------------
Mouse 42-60 inhalation 0, 50, 100, or 200 mg/m3; no pulmonary tumours at Horton
three l-h periods/week, 0-100 mg/m3 et al.
for 35 weeks (1963)
Mouse 36 inhalation 50 mg/m3 for 35 weeks no pulmonary tumours Horton
+ 150 mg/m3 for 29 weeks; et al.
three l-h periods/week (1963)
in addition
Mouse 26 inhalation 100 mg/m3; three 1-h formaldehyde did not modify Horton
periods/week for 35 weeks the pulmonary carcinogenesis et al.
followed by a coal-tar of coal-tar (1963)
aerosol for 35 weeks
Mouse: 119-121 inhalation 0, 2.4, 6.72, or 17.16 mg/m3; squamous cell carcinoma of Kerns
B6C3F1 (male) 6 h/day, 5 days/week, for the nasal cavity in 2 males et al.
119-121 up to 24 months; 6-month (at high exposure only) (1983)
(female) follow-up
Mouse: 29-99 ingestion 0 or 0.5 HMT in drinking- no increased tumour Della
CTM, SWR (male) water for 60 weeks or 5% incidence Porta
+C3Hf 27-100 for 30 weeks (CTM only); et al.
(female) follow-up for 110-130 weeksa (1968)
Mouse: 39 subcutaneous 5 g/kg on alternate days, no increased tumour Della
CTM (male) for 110-130 weeksa incidence Porta
44 et al.
(female) (1968)
Mouse 60 Injection µl "formol oil" 50 times no tumoursd Klenitzky
(route not to the cervix uteri (dose (1940)
described) not defined)
----------------------------------------------------------------------------------------------------------
Table 29 (contd).
----------------------------------------------------------------------------------------------------------
Mouse: 30 topical, 3.7% formaldehyde formaldehyde is probably Spangler
SENCAR (female) back skin in acetone not a complete carcinogen & Ward
once a week, 48 weeks or an initiator (1983)
(preliminary findings only)
Mouse: 30 subcutaneous 0.1-1.0 mg, no incidence of initiator/ Krivanek
CD-1 (female) 3 times a week promotor activity et al.
for 180 days (preliminary findings) (1983a)
Mouse 16 topical, 200 µg 1% or 10% no tumours Iversen
(male) back skin sol., twice a week, (1986)
16 60 weeks
(female)
Rat: 100 inhalation 17 mg/m3 (14.2 ppm); 382 10 squamous cell carcinomas Albert
Sprague (male) exposures over a 588-day of the nasal cavity et al.
Dawley period; 6 h/day, 5 days/week (significantwith regard (1982)
to controls (preliminary
findings only)
Rat: 99 inhalation 16.80 mg/m3 (14.7 ppm) 25/99 squamous cell Albert
Sprague formaldehyde + 14.80 mg/m3 carcinomas of the nasal et al.
Dawley (10.6 ppm) HCl (BCME estima- cavity and 3 papillomas (1982)
ted 1 µg/m3), 6 h/day,
5 days/week, for life
Rat: 100 inhalation 17.16 mg/m3 (14.3 ppm) 12 squamous cell carcinomas Albert
Sprague (male) formaldehyde + 14 mg/m3- of the nasal et al.
Dawley (10 ppm) HCl (pre-mixed); cavity (significant (1982)
378 exposures over 588 days; with regard to controls)
6 h/day, 5 days/week (preliminary results only)
Rat: 100 inhalation 16.92 mg/m3 (14.1 ppm) for- 6 nasal (significant with Albert
Sprague (male) maldehyde + 13.30 mg/m3 (9.5 regardto controls) et al.
Dawley ppm) HCl (not pre-mixed); (5 squamous cell (1982)
378 exposures over 588 days; carcinomas, 1 adenocarcinoma)
6 h/day, 5 days/week (preliminary results only)
----------------------------------------------------------------------------------------------------------------------
Table 29 (contd).
----------------------------------------------------------------------------------------------------------------------
Species/ Number of Route of Dosage Findings Reference
Strain animals exposure
(sex)
----------------------------------------------------------------------------------------------------------------------
Rat: 119-121 inhalation 0, 2.4, 6.72, or 17.16 mg/m3; non-significant polypoid Kerns
F-344 (male) for up to 24 months; 6 h/ adenoma at all doses; 2/235 et al.
119-121 day, 5 days/week; 6-month (non-significant) and 103/232 (1983)
(female) follow-up (significant) squamous cell
carcinomas of nasal cavity,
at the medium and high
doses, respectively
(see also Table 30)
Rat: 32 inhalation 0.36, 2.4, or 17 mg/m3; rhinitis; epithelial cell Tobe
F-344 6 h/day, 5 days/week, for hyperplasia; squamous et al.
28 months metaplasia at 17 mg/m3, 14/ (1985)
32 squamous cell carcinomas
(P < 0.01) and 5/32
papillomas (P < 0.05)
Rat: 100 inhalation 18.24 mg/m3 (15.2 ppm) for- 13 polyps/papillomas; 45 Sella-
Sprague (male) maldehyde + 13.86 mg/m3 (9.9 squamous cell carcinomas; kumar
Dawley ppm) HCl (pre-mixed) (BCME, 1 adenocarcinoma et al.
0.1-0.4 µg/m3); 6 h/day, 1 fibrosarcoma; esthesic (1985)
5 days/week, for life neuroepithelioma resp
Rat: 100 inhalation 17.88 mg/m3 (14.9 ppm) for- 27 squamous cell carcinomas; Sella-
Sprague (male) maldehyde + 13.58 mg/m3 (9.7 2 adenocarcinomas; 11 kumar
Dawley ppm) HCl (not pre-mixed);6 h/ polyps/papillomas et al.
day, 5 days/week for life (1985)
Rat: 100 inhalation 17.76 mg/m3 (14.8 ppm) for- 38 squamous cell carcinomas; Sella-
Sprague (male) maldehyde; 6 h/day, 5 days/ 1 fibrosarcoma; 1 mixed car- kumar
Dawley week, for life cinoma et al.
(1985)
Rat 30 stomach tube 0.4 g/daya, for 333 days no treatment-related tumours Brendel
(1964)
---------------------------------------------------------------------------------------------------------
Table 29 (contd).
---------------------------------------------------------------------------------------------------------
Rat: 48 ingestion 1% HMT in drinking-water no increased tumour Della
Wistar (male) for 104 weeks, for 3 yearsa incidence Porta
48 et al.
(female) (1968)
Rat: 280 ingestion 0, 1.2, 15, or 81 mg/kg bw no tumours (except 1 skin Til
Wistar (male) (males); 0, 1.8, 21, or 109 mesenchymoma in high-dose et al.
280 mg/kg bw (females) male) (1988)
(female) (drinking-water, 2 years)
Rat: 80 ingestion 0, 10, 50, or 300 mg/kg bw; no significant increase in Tobe
Wistar (male) (drinking-water, 2 years) tumours et al.
80 (1988)
(female)
Rabbit 6 oral tank 3% formalin, 90 min, 2/6 leukoplakiasb Mueller
5 times/week for 10 months et al.
(1978)
Syrian 88 inhalation 12 mg/m3, 5 h/day, no increase in Dalbey
golden 5 day/week, lifetime tumour incidence (1982)
hamsters
Syrian 50 inhalation 36 mg/m3, 5 h/day, no increase in nasal Dalbey
golden 5 day/week, lifetime tumour incidence (1982)
hamsters (with diethylnitrosamine)
Rat 10 subcutaneous 1 ml/week for 15 months 4/10 injection-site sarcomas Watanabe
0.4% solution et al.
(1954)
Rat 20 subcutaneous 1-2 ml/week till tumour 7/20 injection-site sarcomas; Watanabe &
development 9-40%a 1/20 injection-site adenoma Sugimoto
(1955)
Rat: 20 subcutaneous 5 g/kg on alternate days, no increased tumour Della
Wistar (male) for 2 yearsa incidence Porta
20 et al.
(female) (1968)
---------------------------------------------------------------------------------------------------------
a Hexamethylenetetramine (HMT) (from which formaldehyde is liberated in vivo).
b Showed "histological features of carcinoma in situ" (Mueller et al., 1978).
c Aspartame (sweetener) was administered to rats at a dosage level of 8 g/kg body weight, which
has been assumed to biodegrade (10%) in the animals yielding 800 mg formaldehyde/kg.
d No tumours, even after treatment with dibenzpyrene and coal tar.
Table 30. Neoplastic changes in the nasal cavities of Fischer 344 ratsa
---------------------------------------------------------------------------------------------------------
Formaldehyde Sex Number of Squamous Nasal Undifferen- Malignant Polypoid Osteo-
mg/m3 (ppm) nasal cell carcinomas tiated sarcomas adenomas chondromas
cavities carcinomas carcinomas/
evaluated sarcomas
---------------------------------------------------------------------------------------------------------
0 (0) male 118 0 0 0 0 1 1
female 114 0 0 0 0 0 0
2.4 (2) male 118 0 0 0 0 4 0
female 118 0 0 0 0 4 0
6.7 (5.6) male 119 1 0 0 0 6 0
female 116 1 0 0 0 0 0
17.2 (14.3) male 117 51c 1b 2b 1 4 0
female 115 52d 1 0 0 1 0
---------------------------------------------------------------------------------------------------------
a From: Kerns et al. (1983) and BGA (1985).
b One animal also exhibited a squamous cell carcinoma.
c 36 of these animals were among the 57 that died prematurely.
d 15 of these animals were among the 67 that died prematurely.
Male rats were exposed to 0, 12, or 24 mg formaldehyde/m3 for 4,
8, or 13 weeks (6 h/day, 5 days/week) and were then observed for
periods of up to 126 weeks (Feron et al., 1987a). Non-neoplastic histo-
pathological changes in the nasal respiratory epithelium (hyper- and
metaplasia) and olfactory epithelium (disarrangement, thinning, and
simple cuboidal or squamous metaplasia) occurred at 24 mg/m3, simi-
lar, but less pronounced, changes of the nasal respiratory epithelium
were seen at 12 mg/m3 and a limited and not statistically significant
number of nasal tumours occurred at 24 mg/m3, mainly in rats that had
been exposed for 13 weeks (6/132: 3 squamous cell carcinomas, 1 carci-
noma in situ and 2 polypoid adenomas).
Feron et al. (1987b) carried out an inhalation study on male rats
with a severely damaged (by electrocoagulation) or undamaged nasal
mucosa. They were exposed to 0, 0.12, 1.2, or 12 mg formaldehyde/m3
6 h/day, 5 days/week, over periods of either 28 months or 3 months,
followed by an observation period of 25 months. A significant number
of nasal squamous cell carcinomas (17/60) occurred only in rats with a
damaged nose that had been exposed to 12 mg/m3 for a period of 28
months.
Basal-cell hyperplasia and/or squamous metaplasia were observed in
the tracheo-bronchial epithelium of C3H mice exposed to 50, 100, or
200 mg formaldehyde/m3, for 4 h/day, 3 days/week, over 35 weeks;
atrophic metaplasia was also observed in the highest dose group (Horton
et al., 1963).
Neoplastic lesions found in the nasal cavities of Fischer 344 rats
exposed to formaldehyde gas are summarized in Table 30 (Kerns et al.,
1983). Several studies were performed to examine whether formaldehyde
acts as a complete carcinogen, a promoter, or an initiator of tumours.
Horton et al. (1963) exposed mice to coal-tar aerosol and to formal-
dehyde (48 or 120 mg/m3, 1 h/day, 3 days/week, over 35 weeks). Coal-
tar aerosol exposure resulted in lung tumour formation, but there was
no evidence of any co-carcinogenic effect of formaldehyde.
8.4.2 Dermal studies
Studies were carried out on mice (Krivanek et al., 1983a; Spangler
& Ward, 1982; Iversen, 1986) to test whether formaldehyde solution
applied to the skin induced papilloma or malignant tumours as an
initiator, or promoter of cancer, or as a complete carcinogen. Formal-
dehyde proved to be neither a complete carcinogen, nor an initiator
(with phorbolmyristateacetate as a promoter). With respect to promoting
activity (with benzo(a)pyrene or dimethylbenyanthracene as an
initiator) the results were either negative or inconclusive. Details
can be found in Table 29.
8.4.3 Oral studies
Some studies were performed using HMT instead of formaldehyde. It
is used as an urinary tract antiseptic and antimicrobial food additive
(Della Porta et al., 1968) and owes its activity to its degradation to
formaldehyde and ammonia in an acid medium (digestive tract) with
conversion of 20% of the theoretical amount of formaldehyde at pH 5
(Goodman & Gilman, 1975).
Slightly reduced growth rate and survival were observed in CTM mice
given 5% hexamethylenetetramine (HMT) in the drinking-water for 30
weeks; a slightly reduced growth rate was also observed in SWR mice
exposed to 1% HMT in the drinking-water for 60 weeks (Della Porta et
al., 1968) (Table 29).
Formaldehyde, and other compounds were tested for tumour-promoting
activity in a 2-stage stomach carcinogenesis study (Takahashi et al.,
1986). Male Wistar rats were given N-methyl- N'-nitro-N-nitroso-
guanidine (MNNG) in the drinking-water (100 mg/litre) and a diet
supplemented with 10% sodium chloride for 8 weeks. Thereafter, they
were maintained on drinking-water containing 0.5% Formalin for 32
weeks. Formaldehyde increased the incidence of adenocarcinoma in the
glandular stomach, after initiation with MNNG and sodium chloride. The
incidence of squamous cell papilloma in the forestomach was signifi-
cantly increased in the groups given formaldehyde, irrespective of
prior initiation. The results indicate that formaldehyde induces
forestomach papilloma and exerts tumour-promoting activity.
Groups of 70 male and 70 female SPF Wistar rats, 31 days old, were
administered formaldehyde at 1.2, 15, or 81 and 1.8, 21, or 109 mg/kg
body weight per day, respectively, as a 5% (w/w) solution in the
drinking-water for up to two years. A group of 70 males and 70 females
served as controls. Groups of 10 rats per sex per group were killed at
weeks 53 and 79 and the remaining animals at week 105. Mortality was
elevated among mid-dose males by the end of the study but there was no
difference among other groups. Mean body weights were lower in high-
dose animals; this was accompanied by a decrease in food and liquid in-
take. The limiting ridge of the forestomach was raised and thickened in
most animals of the high-dose group at each interim killing and at the
end of the study; a similar effect was observed in some other treated
groups and occasionally in controls. Papillary epithelial hyperplasia,
hyperkeratosis, and focal ulceration in the forestomach were observed
in high-dose animals as were chronic atrophic gastritis, ulceration,
and hyperplasia in the glandular stomach. In addition, a higher inci-
dence and degree of renal papillary necrosis was seen in high-dose
animals at the end of the study compared to other treated groups and
controls. One mesenchymoma of the skin was observed in a high-dose male
killed at 52 weeks and two gastric papillomas were observed, one in a
low-dose male and one in a female control, at the end of the study. No
other gastric tumours were reported and no treatment-related tumours
were found (Til et al., 1988).
A similar study was carried out on Wistar rats administered formal-
dehyde in the drinking-water (Tobe et al., 1989). Groups of 20 male
and 20 female Wistar rats, four weeks old, were administered 10, 50, or
300 mg formaldehyde/kg body weight per day as 0.02, 0.1, or 0.5%
solutions, respectively, in the drinking-water for up to 2 years. A
group of 20 males and 20 females served as controls. Groups of 6 rats
per sex per group were killed at 12 and 18 months and the remaining
surviving animals were killed at 24 months. Mortality was elevated in
the high-dose group and reached 45% and 55% in males and females,
respectively, at 12 months; all animals in this group had died by 21
months (females) and 24 months (males). Body weight gain and food and
liquid intake were significantly reduced in high-dose animals.
Erosions, ulcers, squamous cell hyperplasia, hyperkeratosis, and basal
cell hyperplasia with submucosal cell infiltration were observed in the
forestomach in animals of both sexes in the high-dose group at
12 months. Erosions, ulcers, and submucosal cell infiltration also
occurred in the glandular stomach among this group at 12 months and
glandular hyperplasia was observed along the limiting ridge of the
fundic mucosa. In the mid-dose group, hyperkeratosis occurred in the
forestomach in one male and one female among animals killed at 18 and
24 months. No such lesion was found in animals in the low-dose group
at any time. There was no significant increase in the incidence of any
neoplastic lesion in any treated group compared with controls. The
types of tumours observed were similar to those that occur spon-
taneously in this strain of rats.
8.5 Mutagenicity and Related End-Points
The mutagenic properties of formaldehyde have been studied in dif-
ferent test systems (Tables 31 and 32). Extensive data have resulted
from the treatment of Drosophila with formaldehyde-treated food
(Auerbach et al., 1977).
In general, the available data show that formaldehyde is mutagenic
in different test systems, especially when high concentrations act
directly on cells (gene and chromosome mutations). Addition of metab-
olizing systems to the assay system tends to reduce the activity of
formaldehyde. The mutagenic effects of formaldehyde in Drosophila
depend on the route of administration. Inconsistent responses were
obtained in in vitro mammalian mutagenicity assays, increases in
mutation frequency being obtained in the mouse lymphoma assays, but not
with Chinese hamster ovary cells.
Positive cell transformation assays have been reported in vitro .
After inhalation of the compound, local DNA adducts were observed in
rats without simultaneous systemic genetic effects (Casanova-Schmitz et
al., 1984b).
Table 31. The genetic toxicology of formaldehyde: in vitro studies
---------------------------------------------------------------------------------------------------------
Assay Strain/type Metabolic Result Comments Reference
activation
---------------------------------------------------------------------------------------------------------
Procaryotes
Escherichia coli WP2 Hcr+ none - Nishioka
WP2 Hcr- + (1973)
Escherichia coli WP2 ± Aroclor + De Flora
WP67 induced rat + et al.
CM871 liver S-9 + (1984)
spot test + strain was not speci-
fied for spot test, nor
was metabolic acti-
vation used
Escherichia coli WP2 uvrA none - Hemminki
et al.
(1980)
Salmonella typhimurium TM677 ± Aroclor + toxicity and mutageni- Temcharoen
induced rat city reduced with S-9 & Thilly
liver S-9 (1983)
Salmonella typhimurium no strain data - Gocke
et al.
(1981)
Salmonella typhimurium Ames; no strain ± hepatic - paraformaldehyde Bruisick
data activation et al.
(1980)
Salmonella typhimurium TA1535, none - De Flora
TA1538, - et al.
TA1537, - (1984)
TA97 -
TA98 -
TA100 -
---------------------------------------------------------------------------------------------------------
Table 31 (contd).
---------------------------------------------------------------------------------------------------------
Salmonella typhimurium TA97 ± Aroclor - effects of S-9 not Hughes
TA98 induced rat and - given; assumed from et al.
TA100 hamster liver S-9 - abstract all strains (1984)
negative
Salmonella typhimurium TM677 ± Aroclor + Donovan
TA97 induced rat + et al.
TA98 liver S-9 + (1983)
TA100 +
Salmonella typhimurium TM677 none + Sarrit
TA100 + et al.
(1983)
Salmonella typhimurium TA98 ± Aroclor + formaldehyde as Connor
TA100 induced rat + formalin (10-15% et al.
UTH8414 liver S-9 - methanol) (1983)
UTH8413 -
Salmonella typhiurium TA1535 none - formalin tested De Flora
TA1537 - (1981)
TA1538 -
TA98 -
TA100 -
Salmonella typhimurium TA98 ± KC500 - negative with S-9 Sasaki
TA100 induced rat + & Endo
liver S-9 (1978)
Salmonella typhimurium TA98 ± rat liver + activity of formal- Oerstavik
TA100 microsomes + dehyde was reduced in & Hongslo
the presence of rat (1985)
liver microsomes
Salmonella typhimurium TA1535 + plasmids none + Yoshimitsu
5310002/psk1002 et al.
(1985)
---------------------------------------------------------------------------------------------------------
Table 31 (contd).
---------------------------------------------------------------------------------------------------------
Assay Strain/type Metabolic Result Comments Reference
activation
---------------------------------------------------------------------------------------------------------
Salmonella typhimurium TA97 ± Aroclor - weak response De Flora
TA102 induced rat + et al.
liver S-9 (1984)
Salmonella typhimurium TA100 ± Aroclor + pre-incubation Simmons
TA102 induced rat procedure et al.
liver S-9 (1986)
Salmonella typhimurium no strain data ± hepatic - Brusick
activation (1983)
Salmonella typhimurium TA100 ± clophen + Schmid
A50 induced rat (weak) et al.
liver S-9 (1986)
Salmonella typhimurium TA102 none - Levin
TA2638 et al.
(1982)
Salmonella typhimurium TA98 ± PCB, KC-100 - formalin; positive in Ishidate
TA100 induced rat strain TA100 without et al.
TA1537 liver S-9 - S-9 (1981)
Salmonella typhimurium TA98 ± Aroclor - Haworth
TA100 induced rat and - et al.
TA1535 hamster liver S-9 - (1983)
TA1537 -
Eucaryotes
Nematode Caenorhapolitis - Point mutation in Moerman &
elalgans unc-22 gene for Baillie
"twitching" on expo- (1981)
sure to nicotine
---------------------------------------------------------------------------------------------------------
Table 31 (contd).
---------------------------------------------------------------------------------------------------------
Neurospora crassa H-59 (repair - + Brockman
deficient) et al.
H-12 + (1981)
Neurospora crassa Ade + Jensen
et al.
(1951)
Drosophila + FA generated ADH Benyajati
mutants et al.
(1983)
Drosophila - - - not susceptible to Auerbach
mutagenicity when fed et al.
formaldehyde in the (1977)
food; mutations on in-
jection into the larvae
Tradescantia - - strain absorption Ma et al.
(micronucleus) + fumigation (1985)
Saccharomyces D4 - + Chanet
cerevisiae D3 + et al.
(recombination) (1975)
Saccharomyces N123 + mitotic Chanet &
cerevisiae recombination Von
(recombination) Borstel
(1979)
Mammalian cell mutation
Mouse lymphoma L5178Y ± hepatic + paraformaldehyde Brusick
activation (1980)
Mouse lymphoma L5178Y TK± ± S-9 + negative on the ad- Dooley
dition of cofactors FDH (1985)
and NAD+
---------------------------------------------------------------------------------------------------------
Table 31 (contd).
---------------------------------------------------------------------------------------------------------
Assay Strain/type Metabolic Result Comments Reference
activation
---------------------------------------------------------------------------------------------------------
Mammalian cell mutation (contd).
CHO cells HGPRT locus none - Hsie et al.
(1978)
CHO cells HGPRT locus ± Aroclor equivocal Stankowski
induced rat (without et al.
liver S-9 S-9) + (1986)
(with S-9
very weak)
CHO cells AS52 locus +
Human lymphoblasts TK6 none + Goldmacher
& Thilly
(1983)
Cell transformation
C3H10T 1/2 none - Ragan &
Boreiko
(1981)
hamster embryo none + Sonner &
Riverdal
(1983)
rat kidney cell none ± formaldehyde trans- Sonner &
formed cells when Riverdal
incubated with TPA (1983)
Balb/C3T3 1/2 none + Brusick
(1983)
BKH-21/C1.13 ± Aroclor + Plesner &
induced rat Henson
liver S-9 (1983)
---------------------------------------------------------------------------------------------------------
Table 31 (contd).
---------------------------------------------------------------------------------------------------------
DNA repair
hamster embryo none + Hatch
cells (SA7 virus) et al.
(enhanced viral (1983)
transformation)
human diploid + nick translation did Snyder &
fibroblasts - not inhibit repair Van Houten
(1986)
DNA cross-linking CHO-KI none + Marinari
et al.
(1984)
DNA assay
DNA-cell binding none ? Kubinski
et al.
(1981)
Unscheduled DNA Hela + Martin
synthesis et al.
(1978)
DNA damage L1210 mouse + DNA-protein cross- Ross
leukaemia cells links et al.
(1981)
Unscheduled DNA rat tracheal epi- none - Doolittle &
synthesis thelial cells Butterworth
(1984)
bronchial epi- none + DNA-protein cross- Grafstrom
thelial and links; single-strand et al.
fibroblast cells breaks in DNA and inhi- (1983)
bited resealing inhi-
bition of DNA repair
(UDS)
human fibroblasts + Levy
et al.
(1983)
---------------------------------------------------------------------------------------------------------
Table 31 (contd).
---------------------------------------------------------------------------------------------------------
Assay Strain/type Metabolic Result Comments Reference
activation
---------------------------------------------------------------------------------------------------------
DNA-protein cross- rat nasal none + Bermudez &
linking epithelium Delahanty
(1986)
Unscheduled DNA rat nasal none - Bermudez &
synthesis epithelium Delahanty
(1986)
Scheduled DNA rat nasal none + Bermudez &
synthesis epithelium Delahanty
(1986)
RNA synthesis rat nasal none - Bermudez &
epithelium Delahanty
(1986)
Cytogenetic assays
Sister chromatid CHO hepatic activation + paraformaldehyde Brusick
exchange et al.
(1980)
Chromosome aberration CHO hepatic activation +
Sister chromatid V79 ± Aroclor + FA induced sister Basler
exchange induced rat chromatid exchanges; et al.
liver S-9 frequency decreased (1985)
± hepatocytes with S-9 to almost
that of control values;
this was shown to be due
to metabolism, not bind-
ing to macromolecules
Sister chromatid human lymphocyte + Garry &
exchange Kreiger
(1981)
Sister chromatid human lymphocyte + Kreiger &
exchange Garry
(1983)
---------------------------------------------------------------------------------------------------------
Table 31 (contd).
---------------------------------------------------------------------------------------------------------
human lymphoblast + TK locus DNA- Craft
TK6 + protein cross-links et al.
(1987)
Chromosome aberration CHO ± metabolic + Natarajan
activation et al.
(1983)
Sister chromatid human lymphocytes none + Bassendow-
exchange stakarska &
Zawadzkakos
(1983)
Sister chromatid CHO none + Obe & Beek
exchange human lymphocytes none + (1979)
Chromosome aberration embryonic kidney none - formalin Kalmykova
culture (1979)
Sister chromatid CHO ± hepatic + metabolic activation Brusick
exchange activation decreased the dose at (1983)
Chromosome aberration CHO - which sister chromatid
exchange activity was
detected
Chromosome aberration human lymphocyte ± clophen + Schmid
Sister chromatid human lymphocyte A50 induced rat + et al.
exchange liver S-9 (1986)
Chromosome aberration CHO cells ± PCB KC-400 + (in Ishidate
induced rat absence et al.
liver S-9 of S-9) (1981)
Chromosome aberration CHO ± Aroclor + Galloway
Sister chromatid CHO induced rat + et al.
exchange liver S-9 (1985)
---------------------------------------------------------------------------------------------------------
Table 32. The genetic toxicology of formaldehyde: in vivo studies
---------------------------------------------------------------------------------------------------------
Assay Strain/type Result Comments Reference
---------------------------------------------------------------------------------------------------------
Cytogenetic assays
Sister chromatid mouse + in female formaldehyde concentrations were Brusick et al.
exchange mice at mid- greater that the target concen- (1983)
and higher trations of 14.4 and 30 mg/litre
dose levels
Chromosome mouse ? formalin (correct CAS number not Kalmykova
aberration given); 24-h and 25-month exposures (1979)
caused insignificant increase in
cells with chromosomal aberrations;
symmetrical translocations in the
germ cells found in the spermato-
cyte stage and increased post-
implantation embryonic mortality
Chromosome CBA mouse - bone marrow + spleen; 0.4 ml ip Natarajan
aberration at doses of 6.25, 12.5, and et al.
Micronucleus CBA mouse - 25 mg/kg (1983)
Micronucleus NMRI mouse - bone marrow; single ip injection Gocke et al.
of 10, 20, or 30 mg/kg; sampled (1981)
at 3 and 6 years; 2 males and 2
females per group
Sister chromatid Fischer rat - 0.6, 7.2, or 18 mg/m3 (0.5, 6, or Kligerman
exchanges/chromosome 15 ppm); 6 h/day, for 5 days et al. (1984)
aberration
---------------------------------------------------------------------------------------------------------
Table 32 (contd).
---------------------------------------------------------------------------------------------------------
Chromosome rat - at week 1 0, 0.6, 3.6, or 18 mg/m3 (0, 0.5, Scott et al.
aberration and 32 months 3, or 15 ppm) paraformaldehyde); (1985)
bone marrow; + 6 h/day, 5 days/week, for 6 months;
at high dose at 4 and 6 months the mitotic index
in lung macro- in the lung cells of all animals,
phage at 1 week including controls had dropped,
and 2 months and the number of cells available
for scoring was inadequate
Unscheduled DNA synthesis
rat - 0.47, 2, 5.9, or 14.8 mg/litre Doolittle &
(tracheal for 1, 3, or 5 days Butterworth
epithelial cells) (1984)
Dominant lethal
mouse - (spermato- mixture of formaldehyde and Fontignie-
gonial chromo- hydrogen peroxide (30 mg/kg, Houbrechts
some) 90 mg/kg) et al.
(1982)
weak dominant number of pregnancies not reduced;
lethal effects no increase in post-implantation
weeks 1 and 6 lethality; number of live embryos
never decreased below 7.4/female;
pre-implantation loss significantly
increased during the whole study,
except for the 5th and 7th weeks
ICR-Ha Swiss - 32, 40, 16, or 20 mg/kg ip; mated Epstein et al.
mouse (8- to 10- for 3 or 8 weeks (females replaced (1972)
week-old males) weekly)
---------------------------------------------------------------------------------------------------------
Table 32 (contd).
---------------------------------------------------------------------------------------------------------
Assay Strain/type Result Comments Reference
---------------------------------------------------------------------------------------------------------
Dominant lethal (contd).
Q-strain - (spermato- 50 mg/kg ip Fontignie-
mouse gonial chromo- Houbrechts
some (1981)
weak dominant no effect was observed on the number
lethal effect of pregnant females; an increase in
embryonic mortality observed in the
first week after treatment is attri-
butable to an increase in the number
of pre- and post-implantation deaths;
only in the 3rd week was the number of
pre-implantation deaths significantly
increased
Spot test
Somatic cell C57B1/6J"Ha" - 6 - 6.1 and 17.8 - 18.1 mg/m3, Jensen & Cohr
mutation mouse 6 h/day, for 3 days (1983)
(T-stock)
---------------------------------------------------------------------------------------------------------
DNA-protein cross-links have been studied in cultures of mammalian
cells. Some DNA strand breakage was reported, but DNA-DNA cross-links
were not observed. Formaldehyde has been shown to induce chromosome
aberrations and sister chromatid exchanges in a number of cell lines.
The results of studies on the induction of sister chromatid exchanges
in human lymphocyte cultures (Kreiger & Garry, 1983) demonstrated that
there was no significant sister chromatid exchange response below an
apparent "threshold" of 5 ml culture medium.
Craft et al. (1987) exposed human lymphoblasts in vitro to various
concentrations of formaldehyde (0-150 µmol/litre x 2 h). Both the
induction of mutations and the formation of DNA-protein cross-links by
formaldehyde are non-linear functions occurring at overlapping concen-
tration ranges. Holding the culture for 24 h resulted in complete
removal of the cross-links.
Definite evidence that formaldehyde may induce mutations in
vivo has not been found. Tests for the induction of sister chromatid
exchanges in mouse bone marrow cells gave equivocal results. Dominant
lethal tests in ICR-Ha Swiss mice were reported to be negative at doses
up to 40 mg/kg; more recent studies on Q-strain mice showed effects,
except during the first and third week, after treatment of males with
50 mg formaldehyde/kg. Micronucleus and chromosomal assays failed to
reveal any formaldehyde-induced lesions in both exposed rats and mice.
The results of a mouse somatic cell mutation assay (spot test) were
also negative for formaldehyde.
Formaldehyde damage induced in DNA in different human cell culture
systems comprised DNA-protein cross-links and DNA single-strand breaks;
these lesions undergo efficient repair by complex mechanisms (Grafstrom
et al., 1984). An earlier finding that formaldehyde may inhibit DNA
repair (Grafstrom et al., 1983) has not been confirmed (Snyder & van
Houten, 1986).
8.6 Reproduction, Embryotoxicity, and Teratogenicity
This topic has been studied in inhalation, feeding, drinking-water,
gavage, and dermal studies. The results are summarized in Table 33.
In a dominant-lethal study, formaldehyde did not appear to affect
spermatogenesis or fertility in mice at single dose levels up to
40 mg/kg body weight (ip) or produce any increases in fetal death or
pre-implantation losses (Epstein et al., 1972).
Yasamura et al. (1983) gave mice doses of 0, 30, 40, or 50 mg
formaldehyde/kg per day by intraperitoneal injection on days 7-14 of
pregnancy. The mean body weight of treated fetuses was lower than
that in the controls, and the incidence of prenatal death was slightly
increased in treated mice. There was a significant increase in the
frequency of abnormal fetuses from treated dams, the major malfor-
mations being cleft palate and malformations of the extremities. Strain
differences were observed.
A teratology study on the rat was undertaken by the Formaldehyde
Council of Canada (Martin, 1985). Twenty-five mated Sprague-Dawley rats
were exposed through inhalation (whole-body exposure) for 6 h/day to
formaldehyde doses of 2.4, 6, or 12 mg/m3, from day 0 to day 15 of
gestation, inclusive. Two control groups were included in the study.
The females used for the study were 13 weeks of age and weighed between
221 and 277 g. Proven males of the same strain and source were used for
mating. The pregnancy rate in all groups was at least 80%. Uterine
parameters, including numbers of corpora lutea, implantation sites,
live fetuses, dead fetuses, and resorptions, fetal weight, sex ratio,
and pre- and post-implantation losses, were unaffected by treatment.
The overall incidence of litters and fetuses with major malformations,
minor external and visceral anomalies, and minor skeletal anomalies
was not affected by treatment with formaldehyde.
Pregnant hamsters were treated with dermal applications of formal-
dehyde solution on day 8, 9, 10, or 11 of gestation (Overman, 1985).
Fetuses were removed on day 15 and were weighed, measured, and examined
for teratogenic effects. The resorption rate increased in the formal-
dehyde-treated groups, but treatment did not significantly affect
weight or length, and no malformations that could be related to treat-
ment appeared. It was concluded that fetal risk due to topical exposure
to formaldehyde was minimal in this model system. However, there is no
information in this study on the amount of formaldehyde actually
absorbed.
Table 33. Reproduction and teratology studies
---------------------------------------------------------------------------------------------------------
Species Route of Number Dosage Time of Effects on offspring/ Remarks Refer-
exposure of animals treatment reproduction ence
Female Male
---------------------------------------------------------------------------------------------------------
Rat inhalation 12 3 0.012 mg/m3 10-15 days 14-15% increase in no data con- Gofmekler
12 3 1 mg/m3 before ges- duration of gestation; cerning ratio et al.
tation increase in body, of pregnancy, (1968)
(females) heart, and kidney litter size;
weight; decrease in insufficient
weight of liver and number of dose
lungs levels
Rat inhalation 12 3 0.012 mg/m3 10-20 days decrease in ascorbic no data concern- Gofmekler
12 3 1 mg/m3 before ges- acid in the whole ing ratio of et al.
tation lower DNA pregnancy, lit- (1968);
embryo; content in fetal liver; ter size; insuf- Pushkina
(females) increase in liver ficient number et al.
ascorbic acida of dose levels (1968)
Rat inhalation 12 3 0.012 mg/m3 10-20 days changes in kidney and no gross Gofme-
12 3 1 mg/m3 before ges- liver; decrease in myo- fetal mal- kler &
tation cardial glycogen; dis- formations Bonashe-
(females) integration of lympho- vskaya
cytesa; involution of (1969)
thymic lymphoid tissuea
Rat inhalation 15 - 0.0005 4 h/day, on sacrifice on day 20; none Sheveleva
mg/litre days 1-19 of increase in number of (1971)
15 - 0.005 gestation preimplantation deaths;
mg/litre no external malfor-
mations; offspring of 6
dams delivered on day
22; at one-month post-
partum, females, but
not males, were shorter;
decrease in mobility of
females
---------------------------------------------------------------------------------------------------------
Table 33 (contd).
---------------------------------------------------------------------------------------------------------
Rat combined 6 3b 0.005 mg/ 6 months; no adverse effects on no information Guseva
inhalation litre and water; 4 h, reproduction; decrease concerning (1972)
and in- - - 0.12 mg/m3; 5 times/week in the amount of macroscopic exa-
gestion 0.01 mg/litre nucleic acid in the mination of
and 0.25 mg/ testes offspring
m3; 0.1 mg/
litre and
0.5 mg/m3
Rat inhalation 334 0.4 mg/m3 4 h/day for decrease in suscepti- female rats; Sanotskii
in 12 6 mg/m3 20 days bility to adverse ef- other chemicals et al.
groups fects on pregnant rats also tested be- (1976)
(compared with non- side formaldehyde
pregnant rats); altered
renal and hepatic func-
tiona, decrease in
blood haemoglobina
Dog ingestion 9-11 - 125 mg/kg 4 days after no adverse findings dams delivered Hurni &
(125 ppm) mating to naturally Ohder
375 mg/kg day 56 (1973)
(375 ppm)
Rat ingestion 16 16 0.16% HMT parents: from no adverse findings dams delivered Natvig
2 to 5 months naturally et al.
of age; off- (1971)
spring: from
birth to 123
days of age
Rat ingestion 12 6 1% HMT in start: at 8 no adverse findings body weight of Della
drinking- weeks of age treated ani- Porta
water during preg- mals was less et al.
nancy and nurs- than controls (1970)
ing F1 treated
until 20 weeks
post-partum
---------------------------------------------------------------------------------------------------------
Table 33 (contd).
---------------------------------------------------------------------------------------------------------
Species Route of Number Dosage Time of Effects on offspring/ Remarks Refer-
exposure of animals treatment reproduction ence
Female Male
---------------------------------------------------------------------------------------------------------
Rat ingestion 2 1 1% HMTc F1, F2, and no adverse findings small number of Della
F3; 2.5 years animals; only Porta
one dose level et al.
(1970)
Rat ingestion 5 2% HMTc P and F1; 2.5 no adverse findings no control Della
years Porta
et al.
(1970)
Mouse stomach 34 - 74 mg/kg days 6-15 of no malformations; Marks
tube per day; gestation toxic for 22/34a et al.
148 mg/kg (1980)
per day;
185 mg/kg
per day
Mouse stomach - 7 100 mg/kg 5 days no effects on sperm a total of 500 Ward
tube sperm per rat et al.
were evaluated (1984)
Hamster dermal 22 0.5 ml of day 8, 9, 10, increased resorp- total of 259 Overman
37% formal- or 11 of tions, but no effects fetuses in 22 (1985)
dehyde sol- gestation on fetal weight or litters
ution (but length and no mal-
no infor- formations
mation on
amount
absorbed)
---------------------------------------------------------------------------------------------------------
a Only after exposure to the high dose.
b Female untreated, male treated.
c Hexamethylenetetramine (HMT) (from which formaldehyde is liberated in vivo).
The results in Table 33 do not show any evidence of the embryo
being unusually sensitive to formaldehyde, and there is no information
to show that formaldehyde is teratogenic in rodents when administered
orally or applied dermally in non-toxic amounts to the dams. Further-
more, the data do not provide any evidence indicating that formaldehyde
causes terata at exposure concentrations that are not toxic for the
adult.
8.7 Mechanisms of Carcinogenicity
8.7.1 Reactions with macromolecules
Formaldehyde reacts readily with a variety of cellular nucleo-
philes, including glutathione, forming adducts of varying stability
(Feldman, 1973; Uotila & Koivusalo, 1974; McGhee & von Hippel, 1975).
The glutathione adduct of formaldehyde is the true substrate of formal-
dehyde dehydrogenase, which catalyzes the oxidation of the adduct
to S-formyl-glutathione (Uotila & Koivusalo, 1974). Reaction products
with DNA, which have been demonstrated in vitro , include adducts
(McGhee & von Hippel, 1975a,b) and DNA protein cross-links (Brutlag et
al., 1969; Doenecke, 1978; Ohba et al., 1979).
Investigations in rats exposed to formaldehyde through inhalation
have shown that formaldehyde induces the formation of DNA protein
cross-links in the nasal respiratory mucosa in vivo (Casanova-Schmitz
& Heck, 1983; Casanova-Schmitz et al., 1984). The concentration-
response curve for DNA protein cross-linking was sublinear below
7.2 mg/m3 (6 ppm) but apparently linear at higher concentrations
(Casanova-Schmitz et al., 1984). In rats depleted of glutathione,
either by simultaneous exposure to acrolain (Lam et al., 1985) or by ip
injection with phorone (2,6-dimethyl-2,5-heptadien-4-one) (Casanova &
Heck, 1987) a significant increase in the yield of formaldehyde-induced
DNA protein cross-links was observed, suggesting that the formaldehyde
dehydrogenase-catalyzed oxidation of formaldehyde is an important
defence mechanism against the covalent binding of formaldehyde with
nucleic acids in the nasal respiratory mucosa.
DNA protein cross-links could not be detected in the bone marrow
of rats exposed to formaldehyde through inhalation (Casanova-Schmitz et
al., 1984; Casanova & Heck, 1987), suggesting that these are formed
only at the site of entry. Minini (1985) found DNA protein cross-links
in the stomach and beginning of the small intestine of rats that had
been administered formaldehyde by gavage. These cross-links were
detected only after the administration of a very high dose of formal-
dehyde (750 mg/kg, i.e., about 3/4 of the LD50) (McGhee & von Hippel,
1975a,b).
8.7.2 Cytotoxicity and cell proliferation
Increased cell replication occurs as a result of the cytotoxic
effects of formaldehyde on the nasal mucosa.
Morphological changes (acute degeneration, swelling, formation of
"dense bodies", and vacuoles in epithelial cells) were described in
the respiratory epithelium of rats after a single 6-h exposure to 18 mg
formaldehyde/m3 (Chang et al., 1983; Swenberg et al., 1983). When such
exposure was repeated 3-5 times, ulceration was observed in the respir-
atory epithelium in most experimental animals. After a 9-day exposure,
reparative hyperplasia and metaplasia were found. At 7.2 mg/m3, hy-
perplasia and slight degenerative changes were still detected. In
contrast, morphological changes could not be proved at 0.6 and 2.4 mg
formaldehyde/m3 (Starr & Gibson, 1985).
Further research clarified the dependence of cytotoxic effects on
the concentration of formaldehyde and on the length of exposure. After
exposing rats to 7.2 or 18 mg formaldehyde/m3 (6 or 15 ppm) for 6 h
per day over 3 days, the rate of incorporation of 3H-thymidine into
the DNA of the respiratory epithelium, 2 h after the end of the ex-
posure, was increased by a factor of 20 or 10, respectively, indicating
increased cell proliferation. On the other hand, no statistically sig-
nificant increase in thymidine incorporation compared with that in the
controls was found in rats after exposure to 0.6 or 2.4 mg/m3 (0.5 or
2 ppm) and in mice after exposure to 0.6, 2.4, or 7.2 mg/m3 (0.5, 2,
or 6 ppm) for 6 h/day over 3 days. Exposure to formaldehyde at
18 mg/m3 (15 ppm) led to thymidine incorporation being increased by a
factor of 8, in mice (Swenberg et al., 1983).
Despite nearly equal doses (concentration x time), significantly
increased effects were observed with exposure to 18 mg/m3, (15 ppm)
for 6 h/day, 5 days/week (= 448 mg/m3 (540 ppm) x h/week) (Kerns et
al., 1983) compared with exposure to 3.6 mg/m3, for 22 h/day,
7 days/week (= 460 mg/m3 (554 ppm) x h/week) (Rusch et al., 1983).
This indicates that formaldehyde concentration is more important than
the accumulated dose (Swenberg et al., 1985).
A slight increase in cell proliferation (3H-thymidine labelling,
18 h after the end of exposure) was observed after a single 6-h inha-
lation exposure of rats to 0.6 or 2.4 mg formaldehyde/m3 (0.5 or
2 ppm), but not after 3 or 9 such exposures carried out on consecutive
days (Swenberg et al.,1985). In contrast, exposure to 7.2 mg/m3 (6 ppm)
6 h/day for 1 or 3 days caused a marked increase in cell turnover,
which did not normalize as it did after exposure to 0.6 or 2.4 mg/m3
(0.5 or 2 ppm).
The results of recent inhalation studies have confirmed that the
concentration rather than the dose determines the severity of the
cytotoxic effects. In a 4-week study, Wilmer et al. (1987) showed that
there were no appreciable differences in the type, degree, and inci-
dence of nasal lesions between rats continuously exposed to 12 mg
(10 ppm) formaldehyde/m3 (66 mg/m3 (80 ppm)/h per day) and those
exposed intermittently to 12 mg/m3 (10 ppm) (33 mg/m3 (40 ppm)/h per
day). Moreover, intermittent exposure of rats to 12 mg/m3 (10 ppm)
(33 mg/m3 (40 ppm)/h per day) induced more severe nasal changes than
continuous exposure to 6 mg/m3 (also 48 mg/m3 (40 ppm)/h per day).
From a subsequent 13-week study (Wilmer et al., 1986), it appeared that
hyperplasia and metaplasia of the nasal respiratory epithelium occurred
in rats intermittently exposed to 4.8 mg/m3 (13 mg/m3 (16 ppm)/h per
day) but did not occur in rats continuously exposed to 2.4 mg/m3 (2 ppm)
(also 13 mg/m3 (16 ppm)/h per day). In a 28-month inhalation study,
male rats with severely damaged (by electrocoagulation) or undamaged
nasal mucosa were exposed to formaldehyde concentrations of up to
12 mg/m3 (10 ppm); exposure to 12 mg/m3 (10 ppm) resulted in a much
higher incidence of nasal tumours in rats with a damaged mucosa (17/60)
than in rats with an undamaged nose (1/29) (Feron et al., 1987).
Small ultrastructural changes were reported in the cell membrane of
nasal ciliated epithelial cells of rats exposed to formaldehyde through
inhalation (Monteiro-Riviere & Popp, 1986). Similar changes were also
found in the controls, but the significance is unclear.
9. EFFECTS ON MAN
9.1 Sources of Exposure
The general population may be exposed to formaldehyde in tobacco
smoke, automobile emissions, from materials used in buildings and
home furnishings, in consumer and medicinal products, and in nature
(section 3).
9.2 General Population Exposure
A large number of occupations are associated with formaldehyde
exposure (Tables 4 and 34).
Table 34. Potential occupational exposure to formaldehydea
-----------------------------------------------------------------------------
Anatomists Glass etchers
Agricultural workers Glue and adhesive makers
Bakers Hexamethylenetetramine makers
Beauticians Hide preserversb
Biologists Histology technicians (assumed to
Bookbinders including necropsy and autopsy
Botanists technicians)
Carpenters Ink makers
Crease-resistant textile Lacquerers and lacquer makers
finishers Medical personnel (assumed to include
Deodorant manufacturers pathologists)
Disinfectant manufacturers Mirror makers
Disinfectors Oil-well workers
Dress shop personnel Paper makersb
Dressmakers Particle board makersb
Drugmakers Pentaerythritol makers
Dyemakers Photographic film makers
Electrical insulation makers Plastic workers
Embalmers Resin makers
Embalming fluid makers Rubber makersc
Ethylene glycol makers Soil sterilizers and greenhouse
Fertilizer makers workers
Fire-proofers Surgeons
Formaldehyde resin makers Tannery workersb
Formaldehyde employees Taxidermists
Foundry employees Textile mordanters and printers
Fumigators Textile waterproofers
Fungicide workers Varnish workersb
Furniture workers Wood-based material workers
Fur processorsb Zoologists
-----------------------------------------------------------------------------
a From: NIOSH (1976a).
b See IARC (1981).
c See IARC (1981).
The most predominant effects of formaldehyde exposure usually
reported in human beings are various kinds of physical symptoms
emanating from the irritation of the mucosa in the eyes and upper
airways as well as the sensitivity of the skin. Sensory reactions are
apparently the most typical effects in the non-industrial indoor
environment. Most human beings are exposed to low concentrations of
formaldehyde (less than 0.06 mg/m3) in the environment and sensory
effects (odour and irritation) are by far the most common response;
symptoms of hyperactivity in the lower respiratory tract may also be
produced.
It should be realized that extrapolation from animal studies to
estimate human response is dubious in most cases and, for some effects,
impossible. Although some effects, e.g., skin reactions may be compar-
able between animals and human beings, other effects, such as pulmonary
function reactions, are more questionable and others, such as sensory
irritation, cannot be compared.
9.2.1 Sensory effects
The odour of formaldehyde is detected and/or recognized by most
human beings at concentrations below 1.2 mg/m3 (1 ppm) (Leonardos et
al., 1969; Gemert & Nettenbreijer, 1977; Fazzalari, 1978; Brabec,
1981). The absolute odour threshold is defined as the concentration at
which a group of observers can detect the odour in 50% of the presen-
tations (from a series of concentrations) (WHO, 1987) and, for formal-
dehyde, it has been shown to be between 0.06 and 0.22 mg/m3 (Feldman
& Bonashkevskaya, 1971; Berglund et al., 1985, 1987; Ahlström et al.,
1986). However, the individual odour detection thresholds cover a wide
concentration range, over two powers of ten, and the distribution is
extremely positively skewed. Berglund et al. (1987) showed that over
a period of one year, the odour detection and odour strength reports
for formaldehyde were consistent for a group of 10 observers. For a
group of 50 observers, they also showed that the 50-percentile detec-
tion threshold for formaldehyde odour (ED50, method of constant
stimuli including blanks) was 180 µg/m3 (145 ppb), the 10-percentile
(ED10) threshold was 25 µg/m3 (20 ppb), and the 90-percentile
(ED90) threshold was 600 µg/m3 (500 ppb).
If formaldehyde is mixed with contaminated indoor air from a
"sick" building, an increase in the odour intensity of the stimulus
mixture is found at formaldehyde concentrations of less than
0.25 mg/m3 while, at higher concentrations, the odour strength remains
largely unchanged (Ahlström et al., 1986). At high concentrations, for-
maldehyde has a distinct and pungent odour.
The difference between odour and irritation concentration may be
noticeable, but there is no evidence that there is a threshold at which
odour is superceded by irritation. However, for most inhaled odorous
compounds, the trigeminal nerve has a higher threshold than the olfac-
tory nerve (Moncrieff, 1955). When the formaldehyde concentration is
increased and affects both the eyes and the nostrils, sensory irri-
tation is first experienced in the eyes, then the odour is perceived,
and finally nasal irritation occurs (Moncrieff, 1955).
In recent studies with short-term exposures, eye irritation was
reported for formaldehyde from a level of 0.06 mg/m3 and irritation of
the respiratory tract, from 0.12 mg/m3 (Niemelä & Vainio, 1981; NRC,
1981). Clinical and epidemiological data show substantial variations
in individual irritant responses to formaldehyde. The sensory effects
of formaldehyde determined for odour and sensory irritation are listed
in Table 35. The table only lists the reports that have included infor-
mation on reasonable experimental control. In evaluating the different
studies, it should be noted that many of the reported elevated lower
limit values for sensory irritation emanate from studies in which the
observers were not exposed to very low concentrations of formaldehyde
or clean air was not included as the control condition.
Anderson (1979) showed that eye, nose, and throat irritation were
reported by 3 of 16 observers exposed for 5 h daily to 0.288 mg formal-
dehyde/m3 and by 15 of 16 observers exposed to 0.96 mg/m3 in an
environment chamber. A direct relationship between concentration and
sensory irritation was observed only above 0.96 mg/m3 and only at the
highest concentration, 1.92 mg/m3, was slight discomfort experienced
(18 on a scale of 100). Bender et al. (1983) evaluated eye irritation
according to the time of detection of the first trace of irritation as
well as according to subjective ranking of severity. Both time and
severity appeared to be functions of formaldehyde concentration;
severity of response was above "slight" only with the highest test
concentration of 1.2 mg/m3 (28 observers).
In a study by Cain et al. (1986), a group of 33 observers judged
the perceived irritation and odour of formaldehyde during 29-min
chamber exposures to concentrations ranging from 0.3 to 2.4 mg/m3.
The sensory irritation increased with time for the lower concentrations
and decreased with time for the highest. This effect was true for irri-
tation of eyes, nose, and throat and the sensitivity proved to be
roughly equal for all three sites. The sensory irritant effect of
formaldehyde at 1.2 mg/m3 was shown to decrease when the chemical
pyridine was injected into the chamber; such sensory interactions occur
in environmentally realistic situations (see Ahlström et al., 1986).
Apart from Cain et al. (1986), Weber-Tschopp et al. (1977) and Bender
et al. (1983) have shown sensory adaptation to occur with longer
exposure durations.
Weber-Tschopp et al. (1977) exposed healthy volunteers (24 men,
9 women) to formaldehyde concentrations ranging between 0.036 and
4.8 mg/m3 air (33 volunteers for 35 min, 48 volunteers for 1.5 min).
Eye blinking rates as well as subjective irritation effects were deter-
mined. The irritation threshold was found to range between 1.2 and
2.4 mg formaldehyde/m3. A similar threshold (1 mg/m3) was found in
other studies (BGA, 1985). Triebig et al. (1980) noted that 9 out of
53 medical student volunteers exposed to formaldehyde concentrations of
between 0.39 and 0.60 mg/m3 for 8 h/week, over 8 weeks, complained of
headaches, a burning sensation in the eyes, sore throat, and annoyance
because of the smell.
Formaldehyde has been identified as one of the chemical components
of photochemical smog. However, photochemical smog is a complex mix-
ture of chemicals in which not all the components have been identified.
Schuck et al. (1966) showed that eye irritation appeared at 0.012 mg
formaldehyde/m3, but the formaldehyde had been generated by
irradiating ethylene or propylene-nitrogen dioxide mixtures. The
authors noted that irritating components other than formaldehyde, such
as peroyzlacyl nitrate, which is also a potent sensory irritant present
in photochemical smog, may have been generated during irradiation.
Since formaldehyde usually appears in complex mixtures in the human
environment (automobile exhaust, photochemical smog, tobacco smoke,
contaminated indoor air), it is evident that the mixture may cause
sensory irritation at much lower formaldehyde concentrations than when
formaldehyde is present alone. For example, Weber-Tschopp et al. (1976)
showed that, during 29-min chamber exposures, formaldehyde concen-
trations of 0.3 mg/m3 in a tobacco smoke environment resulted in
moderate, strong, or very strong eye irritation.
It has been shown that sensory irritation is the earliest human
reaction to formaldehyde, both in exposure studies and from complaints
about indoor environments. An expert committee at the US National
Academy of Sciences (NRC, 1980) calculated that less than 20% of an
exposed human population would react to concentrations of less than
0.3 mg/m3 with slight sensory irritation of the eyes, nose, and
throat, and possibly also with a slight decrease in mucosal
secretion/flow in the nose (Newell, 1983). Since differences in indi-
vidual reactions to formaldehyde are large in both the normal popu-
lation and in hyperreactive and sensitized persons, it is difficult to
estimate a concentration guaranteed not to produce negative reactions
in the general population.
Table 35. Sensory effects of formaldehyde on man
---------------------------------------------------------------------------------------------------------
Type of Exp. Method Site Conc. (No. stim- Length No. Irritant Effect Refer-
exposure control range uli) conc. of volun- and odour ence
mg/m3 in air stimulus teers detection
(ppm) mg/m3 (ppm) (sex) (d) thres-
holds mg/m3
(ppm)
---------------------------------------------------------------------------------------------------------
30-m3 - Constant Eye 0.04-4.8 (4)
chamber stimuli (0.03-4) 0.04; 1.2; 1 1/2 35 (M) 1.2-2.4 Eye Weber-
2.4; 3.6; min 13 (F) (1-2 ppm) irritation Tschopp
4.8 (0.03; (short et al.
1; 2; 3; 4) exposure) (1977)
---------------------------------------------------------------------------------------------------------
30-m3 - Constant Eye 0.04-4.8 (4)
chamber stimuli (0.03-4) 0.04; 1.2; 37 min 24 (M) 1.2-2.4 Eye Weber-
2.4; 3.6; (long 9 (F) (1-2 ppm) irritation Tschopp
4.8 (0.03; continuous et al.
1; 2; 3; 4) exposure) (1977)
---------------------------------------------------------------------------------------------------------
17-m3 alu- - Constant Eye 0.01-1.2 (5) 6 min 5-28 0.46-1.1 Slight eye Bender
minium smog stimuli (0.01-1) 0; 0.4; 0.7; (0.38-0.9 irritation et al.
chamber 0.8; 1.1; 1.2 ppm) (1983)
equipped (0; 0.35; 1.2 (1.0 Severe eye
with 7 0.56; 0.7; ppm) irritation
sets of 0.9; 1.0)
eye ports
---------------------------------------------------------------------------------------------------------
Chamber 23 ± 0.5 Constant Eye 0.3-2.0 (4) 5 min 1.0 Eye, nose Andersen &
°C stimuli throat 0.3; 0.5; 11 (M) and throat Mölhave
50 ± 5% RH nose 1.0; 2.0 5 (F) irritation (1983)
---------------------------------------------------------------------------------------------------------
Exposure 22 + 1 Limit 0.06-1.15 (7) 6 second 0.06 Ahlström
hood °C with 0.06; 0.10; 8 (M) (50% d) - et al.
Pyridine forced nose 0.17; 0.28; 14 (F) 0.20 (1986)
as master choice 0.46; 0.77; (100% d)
stimulus responses 1.15
---------------------------------------------------------------------------------------------------------
9.2.2 Toxic effects
The clinical features of toxicity are weakness, headache, abdominal
pain, vertigo, anaesthesia, anxiety, burning sensation in the nose and
throat, thirst, clammy skin, central nervous system depression, coma,
convulsions, cyanosis, diarrhoea, dizziness, dysphagia, irritation and
necrosis of mucous membranes and gastrointestinal tract, vomiting,
hoarseness, nausea, pallor, shock, and stupor. Respiratory system
effects caused by high formaldehyde concentrations are pneumonia,
dyspnoea, wheezing, laryngeal and pulmonary oedema, bronchospasm,
coughing of frothy fluid, respiratory depression, obstructive tracheo-
bronchitis, laryngeal spasm, and sensation of substernal pressure.
Coagulation necrosis of the skin, dermatitis and hypersensitivity,
lachrymation and corrosion of the eyes, double vision, and conjuncti-
vitis can occur. Acute ingestion may cause renal injury, dysuria,
anuria, pyuria, and haematuria, and lead to an increase in formate
levels in the urine. Death is due to pulmonary oedema, respiratory
failure, or circulatory collapse (Hallenbeck & Cunningham-Burns,
1985).
Kline (1925) reported 12 cases where ingestion of formaldehyde (a
few drops to 89 ml of concentrated solution) led to death. The largest
amount ingested from which a patient has recovered is 120 ml. A 60-
year-old man swallowed 60-90 ml of a 40% formaldehyde solution. Thirty
hours after death, the mucosa of the lower part of the oesophagus,
stomach, and first portion of duodenum were dark chocolate brown in
colour and of the consistency of leather. All organs and tissues in
contact with the stomach were "hardened" to a depth of about 8 mm
(Levison, 1904).
Allen et al. (1970) reported corrosive injuries of the stomach due
to formaldehyde ingestion.
9.2.3 Respiratory effects
No cases of death from formaldehyde inhalation have been published.
There are numerous reports that exposure to formaldehyde vapour causes
direct irritation of the respiratory tract. However, precise thresh-
olds have not been established for the irritant effects of inhaled
formaldehyde but, within the range of 0.1-3.1 mg/m3, most people
experience irritation of the throat (Table 35).
The effects of formaldehyde on ciliary movement and mucociliary
clearance were studied by Andersen & Mölhave (1983). They measured
nasal mucociliary flow by external detection of the motion of a radio-
labelled resin particle placed on the surface of the inferior turbi-
nate. The nasal mucous flow rate in the nose decreased during exposure
to formaldehyde, but the response did not increase at concentrations
ranging from 0.5 mg/m3 to 2 mg/m3 or on prolongation of the exposure
period from 3 h to 5 h.
The potential of formaldehyde to produce chronic respiratory tract
disease was studied by Yefremov (1970). At a wood-processing plant,
the incidence of chronic upper respiratory disease was higher in 278
workers exposed to formaldehyde than in 200 controls. However, formal-
dehyde concentrations were not measured, and possible confounders were
not evaluated.
Forty-seven subjects exposed to formaldehyde (mean air concen-
tration 0.45 mg/m3) and 20 unexposed subjects, all of whom were
employed at a carpentry shop, were studied by Alexandersson et al.
(1982) with regard to symptoms and pulmonary function. Symptoms
involving the eyes and throat as well as chest oppression were signifi-
cantly more common in the exposed subjects than in the unexposed
controls. Spirometry and simple breath nitrogen washout were normal
on the Monday morning, before exposure to formaldehyde. A reduction
in forced expiratory volume in 1 second by an average of 0.2 litres
(P = 0.002), percent forced expiratory volume by 2% (P = 0.04),
maximum mid-expiratory flow by 0.3 litre/second (P = 0.04) and an
increase in closing volume in percentage of vital capacity by 3.4%
(P = 0.002) were seen after a day of work and exposure to formal-
dehyde, suggesting bronchoconstriction. Smokers and nonsmokers
displayed similar changes in spirometry and nitrogen washout.
Schoenberg & Mitchell (1975) performed standardized respiratory
questionnaire and pulmonary function tests (FVD, FEV1, MEF 50%) on
63 employees in an acrylic-wool filter department (40 production line
workers, 8 former production line workers, and 15 employees who had
never been on the production line). Formaldehyde levels in the work
environment were between 0.5 and 1 mg/m3, and phenol levels, between
7 and 10 mg/m3; particles and fibres were not well suppressed. In
spite of the high proportion (85%) of subjects reporting acute respir-
atory symptoms, only small and insignificant changes in pulmonary
function were found.
Andersen & Mölhave (1983), in a study of 16 healthy volunteers in a
chamber, could not find any increase in airway resistance or any
effects on vital capacity and maximum expiratory flow volume from
exposure to formaldehyde levels of up to 2.0 mg/m3 in a 5-h study.
To study pulmonary function during and after exposure to formal-
dehyde, Schachter et al. (1986) exposed 15 non-smoking healthy volun-
teers (mean age, 25.4 years) in a double-blind random manner to 0 or
2.4 mg formaldehyde/m3, for 40 min on one day and again on a second
day but with the subjects performing moderate exercise (450 kpm/min)
for 10 min. No significant bronchoconstriction was noted (FEV1 test),
and subjective complaints following such exposure were confined to
irritative phenomena of the upper airways. Post-exposure symptoms (up
to 24 h following exposure) were infrequent and confined to headache.
Another study by the same group (Witek et al., 1986, 1987) on
15 healthy and 15 asthmatic volunteers resulted in similar findings.
Main & Hogan (1983) examined 21 subjects exposed to formaldehyde
(0.14-1.9 mg/m3) in a mobile home trailer. Eighteen unexposed con-
trols were included. No differences in lung function were found between
the 2 groups. However, there were significantly more complaints of eye
and throat irritation, headache, and fatigue among the exposed.
In controlled studies, Day et al. (1984) exposed 18 volunteers to
a formaldehyde concentration of 1.2 mg/m3. Nine subjects had pre-
viously complained of various non-respiratory adverse effects from the
urea formaldehyde foam insulation (UFFI) in their homes. Pulmonary
function was assessed before and after exposure in a laboratory. Each
subject was exposed, on separate occasions, to formaldehyde at
1.2 mg/m3 in a environmental chamber for 90 min and to UFFI off-gas
yielding a formaldehyde concentration of 1.4 mg/m3 in a fume hood for
30 min. None of the measures of pulmonary function used showed any
clinically or statistically significant responses to the exposure
either immediately or 8 h after, commencement of exposure. There were
no statistically significant differences between the responses of the
group that had previously complained of adverse effects and of the
groups that had not. There was no evidence that either formaldehyde or
UFFI off-gas behaved as a lower airway allergen or important broncho-
spastic irritant in this heterogeneous population but, because of the
small number of persons under study, it cannot be excluded.
Fifteen non-smoking volunteers (mean age, 25.1 years) who suffered
from substantial bronchial hyperreactivity, were studied by Harving et
al. (1986). The mean provocation concentration of histamine producing
a 20% decrease (PC20) in peak expiratory flow rate was 0.37 g/litre
(standard deviation (SD) = 0.36). All except one patient regularly
required bronchodilator treatment. None used methylxanthines or
corticosteroids. They were exposed to formaldehyde once a week for 3
consecutive weeks. The studies were carried out in a double-blind
random fashion, under controlled conditions, in a climate chamber with
particle-free air. All underwent the same 3 treatments, being exposed
to mean formaldehyde concentrations of 0.85 mg/m3 (SD = 0.07),
0.12 mg/m3 (SD = 0.07), and zero. The mean exposure time at a steady-
state concentration was 89.4 min (SD = 9.5). Bronchodilator drugs were
withheld for 4 h before the studies. During the exposure, each par-
ticipant rated his symptoms of asthma every 15 min on a visual analogue
scale, and forced expiratory volume in one second was measured on a
spirometer every 30 min.
Before and after exposure to formaldehyde, functional residual
capacity and airways resistance were determined in a body plethys-
mograph, and flow-volume curves were measured. Immediately after
exposure, a histamine challenge test was performed.
No significant changes in forced expiratory volume in one second,
airways resistance, functional residual capacity flow-volume curves, or
subjective ratings of symptoms of asthma were found in the group as a
whole, or among the 9 participants with high histamine reactivity
(PC20 < 0.50 mg/ml). Histamine challenge tests were highly reproduc-
ible and were unaffected by exposure to formaldehyde. No appreciable
symptoms were reported after exposure.
Asthma-like symptoms have been elicited by irritant concentrations
of formaldehyde. Precise thresholds have not been established for the
irritant effects of inhaled formaldehyde. However, lower airway and
pulmonary effects are likely to occur between 6 and 36 mg/m3, inde-
pendent of confirmed sensitization.
Several studies have addressed the problem of the mobile home
situation, especially in Canada and the USA, without measurements of
other confounders (section 9.2.8).
9.2.4. Dermal, respiratory tract, and systemic sensitization
Formaldehyde is a known sensitizer for the skin (DFG, 1987), but no
thresholds for induction of dermal, respiratory tract, or systemic
sensitization have been reliably determined.
9.2.4.1 Mucosal effects
Wilhelmsson & Holmström (1987) investigated possible mechanisms
underlying nasal symptoms in 30 formaldehyde-exposed workers in a
factory producing formaldehyde. The mean concentration of airborne
formaldehyde was somewhat below 1 mg/m3, but there were higher peak
values. About 40% of the workers had rhinitis with nasal obstruction
and discharge associated with the work place. The sera of the subjects
were analysed for IgE antibodies by RAST and 2 workers were found to be
positive with a high level of IgE.
There is no evidence in the literature of allergic reactivity of
the mucous membranes of the eyes being caused by airborne formaldehyde
or by formaldehyde solutions. There are only a few case reports about
asthmatic symptoms caused by formaldehyde.
9.2.4.2 Skin effects
Allergic sensitization is caused by formaldehyde in solution only,
not by gaseous formaldehyde. Prolonged and repeated contact with liquid
solutions can cause skin irritation or allergic contact dermatitis,
including sensitization. It is not known whether dermal reactions occur
in human beings from airborne exposure to formaldehyde.
Formaldehyde allergy may be associated with the use of disinfec-
tants, formaldehyde-based plastics, and contact with textiles impreg-
nated with formaldehyde-based resins. Patch-test studies with different
concentrations of formaldehyde have shown that concentrations below
0.05% rarely elicit an allergic reaction, even in sensitive individuals
(Schulz, 1983). Marzulli & Maibach (1973) reported that one of 5 sen-
sitized volunteers reacted, under controlled conditions, to a challenge
concentration of 0.01% formaldehyde.
Formaldehyde solution is a primary skin-sensitizing agent inducing
allergic contact dermatitis (Type IV, T-cell mediated delayed hypersen-
sitivity reaction); it may induce immunological contact urticaria
(Type I, perhaps IgE mediated, immediate hypersensitivity reaction).
Patch tests performed with formaldehyde challenge concentrations of
1% or less resulted in positive reactions in about 2% of all patients
tested throughout the world; higher formaldehyde challenge concen-
trations may be irritant (Anon., 1987).
There are geographical and demographical differences in the inci-
dence of contact sensitivity to allergens. The Japanese Contact
Dermatitis Research Group (1982) published a study dealing with the
results of patch tests performed at 17 Japanese hospitals in 1981. A
total of more than 900 patients and healthy volunteer subjects were
patch-tested with 2% formaldehyde solution (10 mg formaldehyde/cm2).
This caused irritation in 2.78% and a delayed reaction in 2.62% of the
patients.
An allergic contact dermatitis reaction was provoked by a dose of
formaldehyde of 0.25 µg/cm2 skin (challenge dose: 50 µg/cm2 with
0.5% percutaneous penetration).
In the past, formaldehyde dermatitis provoked by clothing textiles
was a problem in certain countries. Modern textile finishing agents
contain N-methylol compounds with only low amounts of free formalde-
hyde, so that formaldehyde allergies due to textiles are no longer
expected to occur (Bille, 1981; Edman & Möller, 1982).
Contact eczema caused by formaldehyde may clear within 1-3 weeks,
even without treatment, when the cause has been recognized and contact
is strictly avoided.
Allergic reactions to cosmetics containing formaldehyde as a pre-
servative, especially shampoos, are unusual (Eckardt, 1966) and appear
mostly among those who have been sensitized by occupational exposure.
In a haemodialysis unit where formalin was used as a sterilant, 6
out of 13 staff members developed dermatitis within 3 weeks (Sneddon,
1968); 4 of the 6 were positive in patch tests with 3% formalin.
9.2.4.3 Respiratory tract sensitization
Well-controlled scientific studies on allergic airway responses to
formaldehyde are few.
Nordman et al. (1985) gave a total of 230 patients, who suffered
from "asthma like" respiratory symptoms, a bronchial provocation test
with formaldehyde. On the basis of the medical and occupational histor-
ies of the patients, the specific bronchial provocation test and other
tests results, 12 cases were considered to be caused by specific sensi-
tization to formaldehyde.
Burge et al. (1985) reported tests on 15 formaldehyde-exposed
workers with symptoms suggesting occupation-related asthma. Bronchial
provocation tests with a mean formaldehyde concentration of
4.8 mg/m3 (range not given) showed 3 subjects with delayed bronchio-
spasm and 6 with an immediate reduction in forced expiratory volume in
one second (FEV1).
In a similar study on 13 patients with asthma suspected of being
related to formaldehyde exposure, no significant drop in FEV was seen
when bronchial provocation tests with formaldehyde concentrations of up
to 3.6 mg/m3 were carried out. Five of the subjects were on broncho-
dilator treatment at the time (Frigas et al., 1984).
Eight cases of occupational asthma (3 smokers, 5 non-smokers) were
reported among 28 members of the nursing staff at a haemodialysis unit
where formalin was used to sterilize the artificial kidney machine
(Hendrick & Lane, 1977). In 2 out of 5 subjects with histories of
recurrent attacks of wheezing, inhalation provocation tests led to
asthmatic attacks similar to those at work.
Hendrick et al. (1982) reinvestigated the nurses of the haemodialy-
sis unit. One nurse had not worked with formaldehyde since 1976 and had
had no further symptoms. Her 1981 test (15-min exposure to 7.2 mg for-
maldehyde/m3) did not provoke any asthmatic response. The other nurse
had continued to work with formaldehyde, though under much improved
conditions, and had continued to suffer mild intermittent attacks of
asthma. Her test (5-min exposure to 3.6 mg formaldehyde/m3) provoked
a late asthmatic reaction similar to the one observed in 1975.
9.2.4.4 Systemic sensitization
A case report has been described involving an anaphylactic shock
reaction after accidental iv application of formaldehyde during
haemodialysis treatment due to formaldehyde remaining in the equipment
after disinfection. No measurements of the residual formaldehyde in
the reconditioned dialyser were given. There was no personal or family
history of atopy. Prick tests and radioallergosorbent tests (RAST)
with common food and inhalant allergens were negative. Prick tests
performed with 0.1 and 1% formaldehyde were positive in the patient,
whereas they were negative in control subjects. The RAST with formal-
dehyde was performed using discs specially prepared and coated with
serum-albumin. RAST was strongly positive. RAST to ethylene oxide was
negative. A patch test with formaldehyde (concentration 1%) was per-
formed and induced an anaphylactic shock, 26 h after the skin appli-
cation of formaldehyde. The patient did not present any anaphylactic
symptoms with the use of non-reconditioned dialysers. An immediate-
type allergy to formaldehyde mediated by IgE may have occurred in this
patient (Maurice et al., 1986). Because, after 26 h, the patch test
resulted in an anaphylactic, but not delayed allergic contact derma-
titis, reaction, the findings seem to be contradictory.
Wilhelmsson & Holmström (1987) investigated possible mechanisms
underlying nasal symptoms in 30 formaldehyde workers exposed through
inhalation in a formaldehyde-producing factory. Two cases showed a
positive RAST with formaldehyde with high total IgE values (177 and
360 kU/litre). One of them suffered from severe rhinitis, the other
from nasal and skin symptoms associated with the work place. A skin
test with formaldehyde was negative at 15 min but positive at 72 h.
Systemic sensitization arising from the release of formaldehyde
into the circulation in chronic haemodialysis patients showed evidence
of formaldehyde-dependent immunization. The production of auto-anti-
nuclear-like antibodies was dependent on the length (years) of the
haemodialysis treatment (Lynen et al., 1983) and on the formaldehyde
concentration released from the dialysers (Lewis, 1981).
Auto-anti-nuclear-like antibodies were found in 5 out of 18
patients after 1 year of dialysis; 10 out of 12 patients after 3-5
years, and in all 9 patients exposed to formaldehyde through dialysis
for more than 5 years (Lynen et al., 1983).
Auto-anti-nuclear-like antibodies were observed in 30% of the
patients when the formaldehyde concentration in the rinse of the
dialysers was 8 mg/litre (8 ppm); however, the incidence was zero at a
concentration of 0.6-1.2 mg/litre (Lewis et al., 1981).
The presence of auto-anti-nuclear-like antibodies and autoimmune
haemolytic anaemia are evidence of Type II autoallergy. Some severe
asthmatic reactions suggest Type I allergy in dialysis patients.
Pross et al. (1987), using a wide range of immunological tests,
studied the effects of controlled short exposures to formaldehyde.
They found a minimal increase in the percent eosinophils, basophils,
and T8 positive cells and a reduction in the response of natural killer
cells to low-dose human alpha-Interferon. According to the authors, the
meaning of these minimal, but statistically significant, changes
remains unclear.
The antigenicity of formaldehyde-treated proteins were reported
70 years ago by Landsteiner & Lample (1917). A study by Patterson et
al. (1986) demonstrated that sera of human beings exposed to
intravenous formaldehyde during dialysis, contained antibodies of
various immunoglobulin classes against formaldehyde-serum-albumin, as
did sera of two dialysis nurses with histories of formaldehyde-induced
asthma.
9.2.4.4.1 Allergic reaction following the dental use of paraformaldehyde
Adverse reactions have been reported following the use of root
canal filling materials containing paraformaldehyde. The extrusion of
a root canal sealant containing paraformaldehyde beyond the apex may be
followed by an allergic reaction in sensitive individuals. The number
of cases is very small in relation to the extensive use of such
materials. However, 3 cases of allergic angiooedema in response to
periapical paraformaldehyde have recently been reported (UK-CSM,
1987).
9.2.5 Skin Irritation
Primary toxic or irritative skin reactions occur through direct
contact with formaldehyde solutions.
The concentration of aqueous formaldehyde solution causing irritant
contact reactions after application on human skin has not been con-
firmed. For human skin, a single application of 1% formalin in water
with occlusion will produce an irritant response in approximately 5% of
the population (Maibach, 1983).
Cosmetics containing a formaldehyde concentration of 0.2% as a pre-
servative and nail hardeners containing at least 5% formaldehyde did
not provoke toxic or irritative contact reactions on normal skin.
Other reactions may occur in cases of previously damaged skin
surfaces and/or atopic individuals.
There are observations but no published experimental or clinical
findings confirming the induction of irritant contact dermatitis by
gaseous formaldehyde (Axelson, 1987, Personal Communication).
9.2.6 Genotoxic effects
Studies on pathology staff, occupationally exposed to formaldehyde,
failed to demonstrate any increase in the incidence of chromosomal
aberrations or the frequency of sister chromatid exchanges (Thomson et
al., 1984). Similarly, there were no increases in the incidence of
chromosomal aberrations in workers exposed to formaldehyde during its
manufacture and processing (Fleig et al., 1982), or in the incidence of
sister chromatid exchanges in workers exposed to formaldehyde in a
paper factory (Bauchinger & Schmid, 1985).
Yager et al. (1986) reported an increased incidence of sister
chromatid exchanges in anatomy students, but the values reported fell
within the normal range. Furthermore, the authors reported that the
subjects were in a "stress situation" at the time of the study and
were also exposed to other agents, including phenol. Bauchinger &
Schmid (1985) reported an increased incidence of chromosomal aber-
rations in a study of workers in a paper factory who were exposed to
formaldehyde; the statistical methods used and the relevance of the
types of aberrations found have been questioned (Engelhardt et al.,
1987).
No increase was found in the mutagenicity of urine of autopsy
workers exposed to formaldehyde (Corren et al., 1985). Ward et al.
(1984) did not observe any effects on sperm morphology or sperm count
attributable to formaldehyde.
Goh & Cestero (1979) studied chromosomal patterns of direct bone
marrow preparations from 40 patients undergoing maintenance haemo-
dialysis. Aneuploidies, chromosomal structure abnormalities, and
chromosomal breaks were seen in the metaphase. During the period of
this study, each patient could have received up to 126 ± 50 mg of
formaldehyde during each dialysis.
9.2.7 Effects on reproduction
Shumilina (1975) reported an increased incidence of menstrual
disorders, mainly dysmenorrhoea, and problems with pregnancy in 446
women workers using urea-formaldehyde resins (130 exposed to work-place
formaldehyde concentrations of 1.4-4.3 mg/m3 and 316 exposed to
concentrations of 0.005-0.67 mg/m3). There were no differences in
fertility between the exposed and control group, but anaemia, toxaemia,
and low birth weight of offspring were more frequent in the exposed
group. However, possible confounding factors were not evaluated in
this study. There is a lack of information on the workers' environment
and the socioeconomic conditions of the study and control groups.
Hemminki et al. (1982, 1983) studied spontaneous abortions among
hospital staff engaged in sterilizing instruments with chemical agents.
They reported that there was no increase in spontaneous abortions
associated with the use of formaldehyde.
In a population of hospital autopsy service workers, 11 exposed
individuals and 11 matched controls were evaluated for sperm count,
abnormal sperm morphology, and 2F-body frequency (Ward et al., 1984).
Subjects were matched for age, and use of alcohol, tobacco, and mari-
juana. Additional information was collected on health, medication, and
other exposures to toxic substances. Ten subjects were employed for
4.3 months (range: 1-11 months) prior to the first sample, and one was
employed for several years. Formaldehyde exposures were episodic, but
with a time-weighted average of between 0.73 and 1.58 mg/m3 (weekly
exposure range, 3.6-48 mg/m3 per h). Samples were taken from exposed
and control subjects 3 times at 2- to 3-month intervals. No
statistically significant differences in the variables were observed
between the exposed and control groups. Reduced sperm count was corre-
lated with increased abnormal morphology and 2F-body frequency in the
exposed group but not in the control group. Evaluation of the impact
of incidental exposures suggests a reduced count with marijuana use and
increased abnormal morphology with medications used by controls. No
effects on sperm due to formaldehyde or its metabolites were observed
in this occupationally-exposed population. However, it was considered
that the lack of an effect in this study might be due to a lack of
statistical power to detect effects at this exposure level.
9.2.8 Other observations in exposed populations
Dally et al. (1981) measured formaldehyde in the air of 100 homes,
containing particle board or urea-formaldehyde foam insulation, in
which residents reported symptoms of eye, nose, and throat irritation.
They found levels ranging from < 0.12 to 4.42 mg/m3 (< 0.1 ppm to
3.68 ppm) and concluded that indoor environmental exposure to formalde-
hyde may exceed occupational exposure levels. Sardinas et al. (1979)
studied individuals from 68 households in which 167 complaints related
to urea-formaldehyde insulation were being investigated. Twice as many
individuals reported eye irritation in homes in which formaldehyde was
detected by Draeger tubes (0.5-10 µg/litre) compared with the number
in homes in which there was no detectable formaldehyde.
In a study by Woodbury & Zenz (1983), 20 symptomatic infants were
followed up, whose mobile home environment was suspected to be related
to their illness. The authors noted a relationship between the occur-
rence of symptoms and the time spent at home. However, no statisti-
cally significant association was found between symptoms and air levels
of formaldehyde.
All three studies suffer from possible selection bias, the absence
of appropriate controls, and no mention of whether other chemical
exposures and smoking habits were considered.
In a pilot study, Schenker et al. (1982) studied the health of 24
full-time residents from 6 homes containing urea-formaldehyde foam
insulation. The results of standardized allergy skin tests and
spirometry tests were normal in all subjects. Memory difficulty was a
frequently reported symptom. Memory storage deficits could not be
demonstrated, but the results of tests of attention span were abnormal
in 11/14 subjects; furthermore, 8 out of the 11 subjects suffered from
elevated depression scores. The sample size in this pilot study was
small (adults: 9 males, 9 females; children: 2 males, 4 females) and
may have been biased by self-referrals; there was no control group.
The Consensus Workshop on Formaldehyde (1984) reviewed several
reports linking long-term formaldehyde exposure to a range of psycho-
logical or behavioural problems (depression, irritability, memory loss,
decreased attentional capacity, sleep disturbances). Most of the
studies used subjective self-report symptom inventories. Control data,
describing the incidence of such symptoms from unexposed persons are
often inadequate or completely absent. Olson & Dossing (1982) adminis-
tered a standardized questionnaire based on the linear analogue self-
assessment method to 70 employees (66 responded) at 7 mobile day-care
centres, in which urea-formaldehyde glued particle boards had been
used, and to 34 (26 responded) employees at 3 control institutions,
selected at random, which did not contain any particle boards. Mean
concentrations of formaldehyde were 0.43 and 0.08 mg/m3, respect-
ively. Among the staff at the mobile day-care centres, there was a
significantly greater prevalence and intensity of symptoms of mucous
membrane irritation, headache, abnormal tiredness, menstrual irregu-
larities, and use of analgesics, but there were no differences in terms
of memory disturbance and concentration (50% of the cohort were
smokers).
Two groups of male workers exposed to formaldehyde (group 1
employed in the phenol-formaldehyde-plastic foam matrix embedding of
fibreglass (batt making); group 2, in the fixation of tissues for
histology) were studied by Kilburn et al. (1985) for work-related
neurobehavioural, respiratory, and dermatological symptoms, and for
pulmonary function impairment. Forty-five male fibreglass batt makers
were studied during the initial work shift after a holiday, with regard
to combined neurobehavioural (impact on sleep, memory, equilibrium, and
mood), respiratory, and dermatological symptoms. Average frequencies
of 17.8 (for the hot areas of the process) and 14.6 (for the cold
areas) were found. Their symptom counts were significantly higher than
those for 18 male histology technicians (average 7.3), and those for
26 unexposed male hospital workers (average 4.8).
The fibreglass batt makers were also exposed to numerous other
products, such as phenol, surfactants, particulate smoke, glass fibre,
etc. The formaldehyde work-place concentrations were not measured. No
consideration was given to potential respondent bias in symptoms or
exposures or to the socioeconomic differences between the workers and
the technicians.
9.2.9 Carcinogenic effects
The evaluation of the risks for human health from occupational or
environmental agents relies heavily on the evidence gleaned from
epidemiological studies. It is, therefore, important to emphasize the
procedures that should be adopted, in order to assess the value of such
epidemiological investigations, particularly with reference to the
shortcomings inherent in the epidemiological method.
For practical purpose, three types of study are in common use: The
cohort, the case-control, and the correlation (surveillance) study.
Cohort and case-control studies relate individual exposure to the agent
under study with the occurrence of a health effect (in this case,
cancer) in individuals, and provide an estimate of relative risk as the
main measure of association. Cohort studies, which follow populations
prospectively, are inherently less subject to bias than the more
commonly used retrospective (historical) cohort studies as the data on
health outcome are not acquired from past records. However, because
retrospective cohort studies cannot be based on a well defined popu-
lation, it is possible to use proportionate mortality (or morbidity)
studies which give, by definition, less precise estimates of risk.
Case-control studies always rely on retrospective exposure assessments
and although such studies are usually easier to execute than cohort
studies, they are sensitive to various types of bias that are difficult
to eliminate. Correlation (surveillance) studies use whole populations
according to geographical area or time period as the initial data base
and health outcome (cause-specific deaths or cancer incidence) is
related to a summary measure of the population exposure. Individual
exposure is not documented, thus causal relationships are difficult to
infer from the results.
All epidemiological studies are subject to some extent to factors
that can affect their quality with, as a general rule, cohort studies
being superior to case-control studies. Four factors are particularly
important: bias, confounding, chance, and qualitative measures of
exposure and outcome. Bias means the operation of factors in the design
or execution of the study that can lead to erroneous associations
between the exposure and the health outcome, because of a failure to
estimate these factors independently. Confounding refers to a situation
in which the relationship between the exposure and the health outcome
is altered by one or more factors that separately and independently
influence the outcome. The likelihood that the results of the study
could have occurred by chance is estimated by using appropriate stat-
istical analyses. Finally, the accuracy and completeness of the infor-
mation gathered on exposure and health outcome needs to be reviewed.
Cancer is a relatively easy outcome to document but epidemiological
studies are often seriously deficient in their assessments of exposure
to the agent of interest, i.e., the degree, the duration, and even the
misclassification of exposure of individual members of the study popu-
lation.
Thus, epidemiological studies need to be evaluated, not only for
their results, but also for the way in which the investigators have
addressed the methodological problem outlined above. Sufficient infor-
mation should be available in the study reports to make these value
judgements.
Thereafter, the reviewer is frequently confronted with a series of
studies from which to make an evaluation. Causality, that is the con-
tention that the agent in question causes the disease in question,
depends on a number of considerations. The most important are: the size
of the relative risk estimate (coupled with a relatively narrow confi-
dence interval), the observation of a putative relationship between
agent and disease in a number of studies using similar or different
designs in different populations; evidence that the agent acts on
specific organ systems which are biologically plausible; and, finally,
that the effect of the agent has been assessed in studies covering an
observation period long enough to allow for the latent period and the
period of induction of disease. In cancer studies, this may require an
observation period of several decades for each study member.
In short, the evaluation of epidemiological studies initially
requires value judgements regarding the quality of the design and
execution of the study. Thereafter an assessment is needed of groups
of studies to estimate the likelihood or otherwise that the relation-
ship between the exposure and the disease is causal. Such evaluation
procedures have been adopted here for formaldehyde and human cancer.
Observed and expected deaths for professional and industrial
workers exposed to formaldehyde are summarized in Table 36. The occu-
pations studied consisted of professionals who use formaldehyde in the
preservation of biological tissues (embalmers, anatomists, pathol-
ogists, and zoologists), and industrial workers involved in the pro-
duction and use of formaldehyde. The pattern and intensity of exposure
to formaldehyde differed for both groups.
Table 36. Observed and expected deaths for professional and industrial
workers exposed to formaldehyde (with 95% confidence limits)a
-----------------------------------------------------------------------------
Cause Professional Industrial
Observed/ Confidence Observed/ Confidence
expected limits expected limits
-----------------------------------------------------------------------------
Cancer
Nasal 0/1.7 0-2.17 0/1.3 0-2.84
Mouth 20/23.8 0.51-1.30 12/9.2 0.67-2.28
Brain 40/22.6 1.26-2.41 6/13.2 0.17-0.99
Lymphatic and
haematopoietic 80/64.0 0.98-1.53 25/30.6 0.53-1.21
Leukaemia 40/27.2 1.05-2.00 9/11.4 0.36-1.50
Other lymphatic
and haematopoietic 40/36.8 0.78-1.48 16/19.2 0.48-1.35
Lung 175/243.6 0.62-0.83 214/227.3 0.82-1.08
Prostate 61/51.6 0.90-1.52 2/0.6 0.40-12.04
Skin 12/11.4 0.54-1.84 0/0.4 0-9.22
Bladder 23/24.3 0.60-1.42 1/0.3 0.18-18.6
Kidney 21/18.6 0.70-1.73 1/0.4 0.06-13.93
Digestive system 211/245.2 0.74-0.98 8/10.4 0.33-1.52
Other causes
Cirrhosis of liver 83/59.3 1.11-1.74 10/9 0.53-2.04
Non-neoplastic
respiratory disease 109/163.7 0.55-0.80 243/241.1 0.88-1.14
---------------------------------------------------------------------------
a From: Consensus Workshop on Formaldehyde (1984).
A summary of epidemiological studies with formaldehyde is presented
in Tables 37, 38, and 39. An excess of several forms of cancer, i.e.,
Hodgkin's disease, leukaemia, cancers of the buccal cavity and pharynx,
lung, nose, prostate, bladder, brain, colon, skin and kidney, has been
seen in more than one of the epidemiological studies relating to
formaldehyde. Some of these excesses may be due to random variation
and others may depend on factors other than formaldehyde exposure.
Such explanations might be suggested, especially when only a few cases
are involved or when the risk ratios are low. Some studies involve the
same populations and therefore do not provide completely independent
information (Marsh, 1983; Wong, 1983; Liebling et al., 1984).
Table 37. Summary of epidemiological proportional mortality rate (PMR) studies with
formaldehydea
-----------------------------------------------------------------------------------------------
Author(s) Study Study Site Risk Decedents Control
(Year) population period estimates Tobacco
(PMR)
-----------------------------------------------------------------------------------------------
Marsh chemical workers 1950-76 136 no
(1982) (USA) respiratory system 80
digestive system 127
genital system 121
lymphatic system 86
Walrath & male embalmers 1925-80 1010 no
Fraumeni (New York) buccal and pharyngeal 126
(1983) nasopharynx -
respiratory 102
nasal -
prostate 89
bladder 92
brain 157
leukaemia 132
colon 140
skin 253
Hodgkins -
kidney 170
lymphatic and haemato-
poietic 115
-----------------------------------------------------------------------------------------------
Table 37 (contd).
-----------------------------------------------------------------------------------------------
Author(s) Study Study Site Risk Decedents Control
(Year) population period estimates Tobacco
(PMR)
-----------------------------------------------------------------------------------------------
Walrath & embalmers 1925-80 1007 no
Fraumeni (California) buccal 131
(1984) respiratory 94
nasal -
prostate 175
brain & CNS 194
leukaemia 175
colon 187
skin 59
Hodgkins -
bladder 138
kidney 100
rectum 102
gallbladder and liver 85
pancreas 135
stomach 79
Stayner garment workers 1959-82 256 no
et al. buccal 229
(1985) nasal Pha. -
digestive 126
gallbladder and liver 313
lung 95
skin 179
bladder and kidney 92
lymphatic 163
leukaemia 168
-----------------------------------------------------------------------------------------------
a Exposure characteristics described.
Table 38. Summary of epidemiological case-control studies with formaldehyde
---------------------------------------------------------------------------------------------------------
Author(s) Study Study Type of Cases Controls Site Risk Comments
(Year) population period exposure
---------------------------------------------------------------------------------------------------------
Jensen physicians 1943-76 speciality 84 252 lung 1.0 -
et al.
(1982)
Odds Ratio
Fayer- chemical wor- 1957-79 levels and 481 481 multiple -
weather kers duration buccal cavity 1.0
et al. oesophagus 0.5
(1983)a,b stomach 1.0
liver, gall-
bladder, 0.9
lung 0.8
Coggon workers 1975-79 occupational 296 472 bronchus 1.5 r.r. 0.9 in
et al. (United higher exposure
(1984)c Kingdom) 1975-79 occupational 132 268 bladder 1.0 r.r. 1.5 in
higher exposure
Olsen workers 1970-82 exposure 754 2465 nasal 2.8 o.r. 1.8 for ex-
et al. (Denmark) assessed nasopharynx 0.7 posure to wood
(1984) dust men
Partanen wood workers 1957-80 levels and 57 171 respiratory 1.3 no exposure-
et al. duration response
(1985)a relationship
Bond chemical wor- 1940-80 ever 308 588 lung 0.6 dose-response
et al. kers exposed relationship
(1986)a
Hayes wood workers 1978-81 levels 91 195 nose and nasal 2.5 low wood-dust
et al. (Netherlands) sinuses exposure
(1986)a 1.9 high wood-dust
exposure
---------------------------------------------------------------------------------------------------------
Table 38 (contd).
---------------------------------------------------------------------------------------------------------
Author(s) Study Study Type of Cases Controls Site Risk Comments
(Year) population period exposure
---------------------------------------------------------------------------------------------------------
Vaughan Tumour regis- 1979-83 occupational 285 552 nasopharynx 1.4 for high exposure
et al. try nasopharynx 2.1 20+ years
(1986a)a buccal cavity 0.6 for high exposure
buccal cavity 1.3 20+ years
Odds Ratio
Vaughan Tumour regis- 1979-83 residential 285 552 nasopharynx 5.5 10+ years
et al. try nasal cavity 0.6 mobile
(1986b)a buccal cavity 0.8 home
Brinton industrial 1970-80 occupational 160 290 nasal cavity 0.4 -
et al. workers
(1984)a
Olsen & Tumour regis- 1970-82 occupational 759 2465 nasal cavity 2.3 squamous cell car-
Asnaes try nasopharynx 2.2 cinoma only; wood
(1986) Denmark dust adencarcinoma
looked for but not
found
Roush Tumour regis- 1940-81 occupational 371 605 nasopharynx 1.1
et al. try nasal cavity 0.8
(1985)
Hardell Tumour regis- 1970-79 occupational 44 541 nasal 6.1 r.r. calculation
et al. try based on 2 exposed
(1982)a Sweden out of 44 nasal
cancers versus
4 out of 541
controls
---------------------------------------------------------------------------------------------------------
a Study controlled for tobacco use.
b Selection criteria < 20 years after first exposure.
c Selection criteria male < 40 years.
Table 39. Summary of epidemiological cohort studies with formaldehydea
---------------------------------------------------------------------------------------------------------
Author(s) Study Study Site Risk Study Type of Comments
(Year) population period estimates popu- exposure
(SMR) lation
---------------------------------------------------------------------------------------------------------
Acheson chemical wor- 1941-81 7680 levels a) lung cancer
et al. kers bucco-pharyngeal 109 and increased with
(1984) nasopharynx - duration level of exposure
lung 95 in one factory
nasal - b) lung cancer not
digestive 101 increased with
larynx 88 cumulative exposure
Harrington male 1974-80 2307 none all brain cancers were
& Oakes pathologists digestive 20 gliomas
(1984) lung 41
bladder 107
brain, CNS 331
lymphatics 54
leukaemia 90
Levine embalmers, 1950-77 1477 none all brain cancers were
et al. (Canada) bucco-pharyngeal 48 gliomas
(1984) lung 94
prostate 88
urinary organs 54
brain, CNS 115
colorectal 85
leukaemia 160
lymphatic 124
digestive 75
---------------------------------------------------------------------------------------------------------
Table 39 (contd).
---------------------------------------------------------------------------------------------------------
Author(s) Study Study Site Risk Study Type of Comments
(Year) population period estimates popu- exposure
(SMR) lation
---------------------------------------------------------------------------------------------------------
Stroup anatomists 1925-79 2317 duration brain cancers were
et al. bucco-pharyngeal 15 special gliomas and increased
(1986) nasopharynx - with duration of
lung 28 employment
nasal -
prostate 100
bladder 68
brain, CNS 270
leukaemia 147
colon 108
lymphatic 123
Blair industrial 1934-80 26 561 levels, exposure-response
et al. workers buccal cavity 96 duration, relationship
(1986) nasopharynx 300 and for prostate and
lung, pleura 111 peaks Hodgkin's disease
nasal cavity 91
prostate 115
bladder 96
kidney 123
brain 81
leukaemia 80
colon 87
skin 80
Hodgkin's 142
Blair industrial 1930-80 26 561 none dose-response
et al. workers nasopharynx 384 relationship for those
(1987) oropharynx 167 also exposed to
particulates
---------------------------------------------------------------------------------------------------------
Table 39 (contd).
---------------------------------------------------------------------------------------------------------
Bertazzi resin workers 1959-80 1332 -
et al. bucco-pharyngeal -
(1986) digestive 156
oesophagus -
stomach 148
lung 236
lymphatic 201
Edling abrasive manu- 1958-83 521 no correlation with
et al. facturers bucco-pharyngeal - exposure
(1987) nasopharynx -
stomach 80
colon 100
pancreas 180
lung 57
prostate 85
lymphatic 200
Stayner textile 1953-77 11 030
et al. workers buccal cavity 343
(1988) digestive system 58
lung 114
bladder 112
kidney 55
brain 71
lymphatic system 91
leukaemia 114
---------------------------------------------------------------------------------------------------------
a There are no cohort studies with control of tobacco use.
In view of the solubility and rapid metabolism of formaldehyde
(section 6.3), it seems that (upper) respiratory tract cancers would
be more likely to be causally related to formaldehyde exposure than
other forms of cancer. Besides various types of occupational exposure,
smoking and other use of tobacco would have to be considered with
regard to potential confounding factors, especially when exerting
strong effects, such as those of tobacco smoking in relation to lung
cancer. Furthermore, because of the formaldehyde contents of mainstream
and side-stream smoke, there would be a potential increase in any
reference population, and this would mask the effects of formaldehyde
with regard to cancers that might be related to occupational or other
specified exposure to formaldehyde. Finally, it should be noted, within
this general epidemiological context, that there is experimental evi-
dence providing a relatively clear suggestion of a possible cancer risk
for human beings from exposure to formaldehyde.
Excess of nasal or nasopharyngeal cancer in relation to formalde-
hyde exposure was reported in 6 of the case-control studies reviewed
(Table 38) (Hardell, 1982; Olsen et al., 1984; Roush et al., 1985;
Hayes et al., 1986; Vaughan et al., 1986a,b). In 2 other case-control
studies (Fayerweather et al., 1983; Brinton et al., 1984), the question
of a relationship with formaldehyde was addressed either by primary
design or by reporting formaldehyde exposure for either cases or
controls, but no excess risk was demonstrated. None of the cohort or
PMR studies listed in Tables 37 and 39 had adequate power to detect
even a considerably increased risk though, in aggregate, the studies
might have had the power to reveal, at least, a higher risk for nasal
cancer. It should also be noted that with regard to nasal and naso-
pharyngeal cancer, smoking is not likely to exert any particularly
strong confounding effect, since the relation of these cancer types to
smoking is only moderately strong, i.e., up to a risk ratio of about
five (Axelson & Sundell, 1978; IARC 1986) and has been lower in many
studies.
Cancers of the buccal cavity and pharynx have either not been
included in studies or in some case-control studies the risk has
appeared about normal (Fayerweather et al., 1983; Vaughan et al.,
1986a,b), There was no excess in the largest cohort (Blair et al.,
1986), though an excess appeared in other studies involving small
numbers (Stayner et al., 1985, 1988; Walrath & Fraumeni, 1983, 1984).
Table 40. Mortality from subsites of cancer of the buccal cavity and
pharynx through cumulative exposure to formaldehydea
---------------------------------------------------------------------------------------------------------
Cancer
Mortality after formaldehyde exposure at:
0 mg/m3-years < 0.6 mg/m3-years 0.6 - 6.6 mg/m3-years > 6.6 mg/m3-years
Observed Expected SMR Observed Expected SMR Observed Expected SMR Observed Expected SMR
---------------------------------------------------------------------------------------------------------
Lip 0 0.1 -b 1 0.2 477 0 0.2 -b 1 0.1 764
Tongue 0 0.5 -b 0 1.8 -b 2 2.1 96 0 1.3 -b
Salivary glands 0 0.2 -b 0 0.5 -b 0 0.6 -b 0 0.3 -b
Gum, floor, other 0 0.4 -b 1 1.5 66 0 1.8 -b 1 1.1 88
mouth sites
Nasopharynx 1 0.2 530 2 0.7 271 2 0.8 256 2 0.5 433
Oropharynx 0 0.3 -b 4 0.9 443c 1 1.0 95 0 0.7 -b
Hypopharynx 1 0.2 594 1 0.6 172 0 0.7 -b 0 0.4 -b
Other parts of 0 0.4 -b 1 1.4 73 0 1.6 -b 0 1.0 -b
pharynx
---------------------------------------------------------------------------------------------------------
a From: Blair et al. (1986).
b No deaths.
c P < 0.05.
Some excess of respiratory cancer has appeared in 3 case-control
studies in comparison with low exposures in general (Coggon et al.,
1984) or comparable unexposed workers (Partanen et al., 1985) and
between physicians in surgery and internal medicine, though these
findings were based on small numbers (Jensen et al., 1982). Two other
studies have come out as non-positive (Fayerweather et al., 1983; Bond
et al., 1986). Of these cohort and PMR studies, which had adequate
power and were designed to elucidate the risk of respiratory cancer
from formaldehyde, 3 (Walrath, 1983; Bertazzi et al., 1986; Blair et
al., 1986) showed an excess (significantly high in the study by
Bertazzi et al., 1986). Blair et al. (1986) showed some excess in
laryngeal cancer (Table 40). Seven studies with reasonable power were
negative (Harrington & Oakes, 1984; Stroup et al., 1984, 1986) or non-
positive with regard to respiratory cancer (Marsh, 1983; Acheson et
al., 1984; Levine et al., 1984; Walrath & Fraumeni, 1984; Stayner et
al., 1985, 1988). The deviations in both directions from the expected
in these studies are explainable by the lack of control for smoking
and/or the so-called "healthy worker effect", which means that the
study population is not comparable with the general population.
Leukaemia has come out somewhat high in all the studies involving
reasonable numbers of cases (Stroup et al., 1984, 1986; Walrath &
Fraumeni, 1983) and even significantly high in one study (Walrath &
Fraumeni, 1984). Three of these studies involved either embalmers
(Walrath & Fraumeni, 1983, 1984) or anatomists (Stroup et al., 1984,
1986), which might suggest some other alternative or contributing
etiological factor operating. Similarly, for brain cancer, which was
found in significant excess in some studies (Harrington & Oakes, 1984;
Stroup et al., 1984, 1986; Walrath & Fraumeni, 1984), a confounding
factor may be suspected regarding the relationship between brain cancer
and social class (Table 41). An excess of colon cancer among embalmers
(Walrath & Fraumeni, 1983, 1984; Stroup et al., 1984, 1986) may perhaps
be explained by a recently observed association with sedentary work
(Garabrant et al., 1984; Gerhardsson et al., 1986). Of the other
cancer forms previously mentioned as appearing in excess in more than
one study, cancers of the skin, bladder, kidney, and prostate, as well
as Hodgkin's disease are represented by small numbers and/or small
excesses, though prostatic cancer was significantly high in one study
on embalmers, based on 23 cases (Walrath & Fraumeni, 1984) and skin,
but not prostatic cancer was significantly high in the other study on
embalmers (Walrath & Fraumeni, 1983).
Table 41. Mortality ratios of men according to social classa
---------------------------------------------------------------------------------------------------
Disease Population Social class Reference
Place Age Year Ratiob High Low
Race (years) I II III IV V
---------------------------------------------------------------------------------------------------
Brain cancer
United Kingdom
all 15-64 1970-72 SMR 108 101 111, 105 100 92 Registrar General (1978)
all 65-74 1970-72 PMR 225 137 109, 99 85 56 Registrar General (1978)
all 20-64 1949-53 SMR 133 96 104 88 99 Registrar General (1978)
all 65 1949-53 PMR 136 112 105 90 71 Registrar General (1978)
all 35-65 1930-32 SMR 167 92 116 97 66 Registrar General (1978)
all 20-65 1921-23 CMFR 160 160 120 80 60 Registrar General (1978)
USA
California
all 20-64 1949-51 SMR 130 127 108 77 58 Buell et al. (1960)
Massachusetts
white 20 1971-73 SMOR 164 97 114 62c Dubrow & Wegman (1984)
USA
all 20-64 1950 SMR 136 121 109 94 81 Guralnick (1963)
Leukaemia
United Kingdom
all 15-64 1970-72 SMR 113 100 107, 101 104 95 Registrar General (1978)
all 65-74 1970-72 PMR 138 124 108, 98 90 77 Registrar General (1978)
all 20-64 1949-53 SMR 123 98 104 93 89 Registrar General (1978)
all 65 1949-53 PMR 202 115 101 78 74 Registrar General (1978)
all 20-65 1930-32 SMR 152 126 97 95 86 Registrar General (1978)
USA
California
all 20-64 1949-51 SMR 104 116 101 86 104 Buell et al. (1960)
Massachusetts
white 20 1971-73 SMOR 126 97 108 89c - Dubrow & Wegman (1984)
USA
all 20-64 1950 SMR 117 100 105 89 98 Guralnick (1963)
---------------------------------------------------------------------------------------------------
a From: Levine (1985).
b SMR = standardized mortality ratio.
PMR = proportional mortality ratio.
SMOR = standardized mortality odds ratio.
CMFR = comparative mortality figure ratio.
c Including classes IV and V.
10. EVALUATION OF HUMAN HEALTH RISKS AND EFFECTS ON THE ENVIRONMENT
10.1 Evaluation of Human Health Risks
The absolute odour threshold for formaldehyde is between 0.06 and
0.22 mg/m3 (a group of observers detected the odour in 50% of the
presentations, 10% of an untrained population detected a level of
0.03 mg/m3). There is a low probability that human beings will be
able to detect formaldehyde in air at concentrations below
0.01 mg/m3.
Since interaction and adaptation processes are characteristic of
the sensory systems involved in the perception of odour and irritation,
the duration of exposure and the other components of environmental air
exposure influence the perception. Although sensory adaptation because
of length of exposure may weaken the perceptual response, there is a
high probability that exposure duration will enhance the perception,
especially at low concentrations. In addition, formaldehyde often
appears in complex gas mixtures that contain other low concentrations
of odorous or irritating components. Examples are photochemical smog,
automobile exhaust, environmental tobacco smoke, and contaminated
indoor air, with building materials as the source.
There are no data on the absolute irritation threshold for
formaldehyde, but sensory irritation has been reported for the eyes at
0.06 mg/m3 and for the respiratory tract at 0.12 mg/m3.
Formaldehyde vapour causes direct irritation of the human respir-
atory tract. However, precise thresholds have not been established for
the irritant effects of inhaled formaldehyde. Some people experience
throat irritation at 0.1 mg/m3 and almost everybody will experience it
before a level of 3.0 mg/m3 is reached.
The effects on the nasal cavity, the site of impact for most of the
inhaled formaldehyde, is impairment of mucociliary flow at or above a
level of 0.5 mg/m3. This effect may also lead to the secondary
complication of respiratory disease. There is a higher incidence of
chronic respiratory disease in occupationally-exposed subjects or
children living in a formaldehyde-polluted environment. Long-term
exposure to 0.45 mg/m3, independent of tobacco-smoking habits, may
cause bronchoconstriction.
Formaldehyde has been shown to cause pulmonary effects on healthy
and on asthmatic subjects (not sensitized to formaldehyde) at a concen-
tration that is already irritant. Precise thresholds have not been
established for the pulmonary irritant effects of inhaled formaldehyde.
However, lower airway and pulmonary effects are likely to occur at
levels above 6 mg/m3.
There are no data on the exact exposure level at which inhaled
formaldehyde has a sensitizing effect, but once sensitization has
developed, short-term exposure to concentrations that can be found in
occupational or home environments is sufficient to produce an asthma-
like response. Asthmatic responsiveness may persist if intermittent
exposure to low levels continues. Removal from exposure has a favour-
able effect on symptoms.
Although few proven formaldehyde-induced asthma patients have been
reported, it appears likely that this condition is underreported.
There is a possibility of the induction of sensitisation via haemo-
dialysis, where formaldehyde may enter the circulation through the
disinfecting of the dialysis equipment. This can be influenced by the
state of health and previous medication of the patient.
Skin sensitisation in human beings is induced by direct contact
with formaldehyde solutions, only in concentrations higher than 2%.
The lowest patch-test challenge concentration producing a reaction in
sensitized persons was 0.05% formaldehyde in an aqueous solution.
Patch tests performed with formaldehyde challenge concentrations of
< 1% formaldehyde resulted in positive reactions in about 2% of all
patch-tested patients throughout the world.
Positive patch tests results with formaldehyde challenge concen-
trations of 2% or more may be due to skin irritation.
Formaldehyde may induce contact urticarial reactions, but these are
rarely observed and have not been confirmed as IgE-mediated Type I
reactions.
Cell-mediated allergic dermatitis, arising from systemic exposure,
and antibody (IgE)-mediated exanthematous phenomena have not been
observed after ingestion of formaldehyde.
Irritant skin reactions occur through direct contact with formal-
dehyde solutions. A single application of 1% formalin in water with
occlusion will produce an irritant response in approximately 5% of the
test population.
Mental or behavioural problems at levels present in the home
environment have been claimed to be due to long-term formaldehyde
exposure, as adjudged by questionnaires, but there were no differences
in terms of memory loss, sleep disturbance, and concentration. Possible
impaired memory, equilibrium, and dexterity, in some cases has been
suggested in relation to long-term, high-level occupational exposure.
Animal data do not indicate that formaldehyde is embryotoxic or
teratogenic.
Formaldehyde reacts with macromolecules, including DNA. The
genotoxic effects of formaldehyde have been reported in a wide range of
mutagenicity tests in vitro in the absence of a metabolizing system.
In vivo , most mutagenicity tests are negative. However, DNA-
protein cross-links are induced at the site of exposure, after inhaling
formaldehyde. The importance of this local genotoxic effect with
respect to the induction of cancer requires further evaluation.
The importance of positive mutagenicity findings with regard to
germ-cell mutations is limited. In the light of known metabolic mech-
anisms, it should not be assumed that formaldehyde induces mutations in
germ cells and it is unlikely that formaldehyde leads to a heritable
genetic risk.
Formaldehyde is a nasal carcinogen in rats. A highly significant
incidence of nasal cancer was induced in rats exposed to a level of
18 mg/m3, but the concentration-response curve was extremely non-
linear, and only a low, not statistically significant, incidence of
nasal tumours occurred at 7.2 mg/m3. The results of this and other
studies consistently indicate that, at low concentrations, the risk of
cancer is disproportionately low. It is likely that defence mechanisms
in the respiratory tract, including the mucociliary clearance appar-
atus, metabolism by formaldehyde dehydrogenase and other enzymes, and
DNA repair, are effective at low concentrations, but that, at high
concentrations, these defence mechanisms can be overwhelmed and may
even be inactivated, thus resulting in tissue damage.
On the basis of these data it can be concluded that the induction
of nasal cancer in rats by formaldehyde requires repeated exposure to
high concentrations, i.e., concentrations that are very irritating and
cause considerable damage to the nasal mucosa followed by regenerative
hyperplasia and metaplasia. The increased cell turnover, as well as
subsequent cycles of DNA-damage provoked by continuous exposure to
formaldehyde, may strongly increase the likelihood of relevant DNA
damage, and subsequently may greatly enhance the progression of pre-
neoplastic cells to cancer. Formaldehyde, in concentrations not leading
to cell damage, probably cannot act as a complete carcinogen, causing
initiation, promotion, and progression, and, as a result, is very
unlikely to induce cancer by itself. From the above, it appears that
the cytotoxic effects are likely to play a highly significant role in
the formation of nasal tumours by formaldehyde.
Despite differences in the anatomy and physiology of the respir-
atory tract between rats and human beings, the respiratory tract
defence mechanisms are similar. Therefore, it is reasonable to conclude
that the response of the human respiratory tract mucosa to formaldehyde
will be qualitatively similar to that of the rat respiratory tract
mucosa.
Evidence from rat studies suggests that recurrent tissue damage
occurs in conjunction with exposure to high, cytotoxic concentrations
of formaldehyde, and that this is necessary for nasal tumours to be
produced. If respiratory-tract tissue is not repeatedly damaged,
exposure of human beings to low, non-cytotoxic concentrations of
formaldehyde can be assumed to represent a negligible cancer risk.
However, if exposure were to be accompanied by recurrent tissue damage
at the initial site of contact, formaldehyde may be assumed to have
carcinogenic potential for man.
Some excess has been shown for several types of cancer in more than
one of the epidemiological studies relating to formaldehyde, i.e.,
Hodgkin's disease, leukaemia, and cancers of the buccal cavity and
pharynx, lung, nose, prostate, bladder, brain, colon, skin and kidney.
Some of these excesses may be due to random variation and others may
depend on factors other than formaldehyde exerting confounding effects.
Such explanations might be suggested, especially when only a few cases
are involved or when the risk ratios are low.
In view of the solubility and rapid metabolism of formaldehyde, it
seems that upper respiratory tract cancers would be more likely to be
causally related to formaldehyde exposure than other forms of cancer,
especially as there is experimental evidence providing a relatively
clear suggestion of a possible cancer risk for human beings from
exposure to formaldehyde. Besides various types of occupational
exposure, smoking and other use of tobacco would have to be considered
as potentially confounding factors, especially when exerting strong
effects, such as those of tobacco smoking in relation to lung cancer.
Furthermore, because of the formaldehyde content of mainstream and
environmental tobacco smoke, there is exposure of any reference popu-
lation, and this would mask effects with regard to cancers that might
be related to occupational or other specified exposure to formal-
dehyde.
Some excess of nasal or nasopharyngeal cancer was reported in
relation to formaldehyde exposure in 6 of the case-control studies
reviewed. In 2 other case-control studies, the question of a relation-
ship with formaldehyde was addressed either by primary design or by
reporting formaldehyde exposure, but no excess risk was demonstrated.
None of the cohort or PMR studies reviewed had adequate power to detect
even a considerable increased risk though, in aggregate, the studies
might have had the power to reveal, at least, a higher risk for nasal
cancer. It should be noted that, with regard to nasal and nasopharyn-
geal cancer, smoking is not likely to exert any particularly strong
confounding effect, since the relationship between these types of
cancer and smoking is only moderately strong, i.e., a risk ratio of up
to about five, and considerably less in many studies.
Cancers of the buccal cavity and pharynx have either not been
included in studies or else the risk has appeared approximately normal
in some case-control studies. There was no excess in the largest
cohort, though an excess had appeared in other studies involving small
numbers.
Some excess respiratory cancer appeared in 3 case-control studies,
but these studies were based on small numbers. Two other studies came
out as non-positive. Four of the cohort and PMR studies that had
adequate power and were designed to elucidate the risk of respiratory
cancer from formaldehyde exposure showed an excess risk (significantly
high in workers producing resins containing formaldehyde, Bertazzi et
al., 1986). There was an excess of laryngeal cancer in one study. Seven
studies with reasonable power were either negative or non-positive with
regard to respiratory cancer. The deviations in both directions from
the expected in these studies are explicable by lack of control for
smoking and/or the so-called "healthy worker effect" due to lack of
comparability of the study population with the general population.
The incidence of leukaemia was increased in all the studies with
reasonable numbers and was significantly high in one study. Three of
these studies involved either embalmers or anatomists, which might
suggest the operation of some other alternative or contributing
etiological factors. Similarly, a confounding effect from some other
factors might be suspected with regard to the relation between brain
cancer (which was found in significant excess in some studies) and
social class. An excess of colon cancer among embalmers must be
considered against a recently observed association between this type of
cancer and sedentary work. Of the other cancer forms previously men-
tioned as appearing in excess in more than one study, cancers of the
skin, bladder, kidney, and prostate, as well as Hodgkin's disease, are
represented by small numbers and/or small excesses. However, in one
study based on 23 cases, prostate cancer was significantly high but not
skin cancer, whereas in another study on embalmers, skin cancer was
significantly high but not prostate cancer.
The available human evidence indicates that formaldehyde does not
have a high carcinogenic potential. There are some studies which indi-
cate an excess of nasal and/or nasopharyngeal tumours in exposed indi-
viduals or population though the relative risks are, in general,
small.
Given the relative rarity of tumours in the biologically plausible
area of the upper respiratory tract, and the widespread past occu-
pational exposures to formaldehyde in various work situations, it can
be concluded that formaldehyde is, at most, a weak human carcinogen.
Human exposure to formaldehyde should be minimized, not only for
its probable carcinogenic effect, but also for its potential for tissue
damage. One practical way of moving towards an effective preventive
strategy would be to control the formaldehyde level in the work place
below that likely to produce a significant irritant effect.
The epidemiological studies on carcinogenicity that contain some
exposure assessments imply that, in the past, working populations show-
ing an excess of nasal epithelial tumours had generally been exposed to
formaldehyde levels in excess of the tissue-damage threshold. Such a
threshold is probably about 1.0 mg/m3 (range 0.5-3 mg/m3).
With regard to atmospheric exposure limit values for odour and
sensory irritation for the general population and the non-industrial
indoor environment, formaldehyde concentrations should not exceed
0.1 mg/m3. In the case of specially sensitive groups that show
hypersensitivity reactions without immunological signs, formaldehyde
concentrations should be kept to a minimum and should not exceed
0.01 mg/m3.
To avoid strong sensory reactions in work-place environments where
formaldehyde is being produced or used, peak concentrations above
1.0 mg/m3 should not be allowed and mean concentrations should be kept
below 0.3 mg/m3.
10.2 Evaluation of Effects on the Environment
Formaldehyde is present in the environment as a result of natural
processes and from man-made sources; the quantities produced by the
former greatly exceed those from the latter. Nevertheless, the
compound should be considered as an environmental contaminant, because
it has been detected at levels higher than background concentrations in
areas influenced by man-made sources. Air is the most relevant compart-
ment in the formaldehyde cycle, as most of the formaldehyde produced
and/or emitted enters the atmosphere and this is also where most of the
degradation processes occur. The half-life of formaldehyde in the air
is short, due to photodegradation. Formaldehyde is also biodegraded in
water and soil in a relatively short time and does not accumulate in
organisms. Data available for ecotoxicological assessment refer almost
exclusively to formaldehyde in water. It can be classified as toxic
for aquatic biota, with a lowest acute effect level for several aquatic
organisms of about 1 mg/litre. However, fish seem to be more tolerant.
No long-term toxicity tests have been performed, but the possibility of
elimination via biodegradation, the low bioaccumulation factor, and the
ability of organisms to metabolize formaldehyde, suggest that its
impact on the aquatic environment would be limited, except in the case
of massive discharge. With regard to the terrestrial environment, the
lack of ecotoxicological data gives rise to concern, because most of
the formaldehyde is distributed in the air. However, it should be
noted that photooxidation in air is the main degradation process and
that the reaction is fast. Data on the effects on plant foliage of
exposure to peak concentrations of formaldehyde could be of relevance
for a complete evaluation, though the highest concentrations detected
have not lasted for very long.
10.3 Conclusions
- Formaldehyde occurs naturally and is a widely produced industrial
chemical.
- Formaldehyde is a product of normal metabolic pathways.
- Formaldehyde undergoes rapid decomposition and does not accumulate
in the environment.
- Major sources of formaldehyde are:
- automobile and aircraft exhaust emissions;
- tobacco smoke;
- natural gas;
- fossil fuels;
- waste incineration; and
- oil refineries.
- Formaldehyde exposure varies widely because of local variations.
Significant levels of formaldehyde have been reported in indoor
air. Among the sources are tobacco smoke, building and furnishing
materials, and disinfectants.
- In work places, exposure may occur during the production or hand-
ling of formaldehyde or products containing formaldehyde.
- The most prominent features of formaldehyde vapour are its pungent
odour and its irritant effects on the mucosa of eyes and upper
airways. Odour-detection thresholds are generally reported to be
in the range of 0.1-0.3 mg/m3.
- Eye and respiratory-tract irritation generally occurs at levels of
about 1 mg/m3, but discomfort has been reported at much lower
levels.
- Direct contact with formaldehyde solutions (1-2%) may cause skin
irritation in approximately 5% of patients attending dematological
clinics.
- Long-term exposure can lead to allergic contact dermatitis; this
has been demonstrated for formaldehyde solution only, not for
gaseous formaldehyde.
- Reversible airways obstruction has been produced by irritant
concentrations of formaldehyde.
- Long-term exposure to formaldehyde at a level as low as
0.5 mg/m3 may cause a slight elevation in airway resistance.
- Formaldehyde-related asthma has rarely been reported despite the
widespread population exposure to formaldehyde.
- To avoid adverse reactions in dental surgery practice, root canal
sealers should not be extruded beyond the apex in short-term
exposure situations.
- There is no convincing evidence that formaldehyde is a teratogen,
in either animals or human beings.
- Formaldehyde has not produced any adverse effects on reproduction
in test animals or in human beings.
- Formaldehyde is positive in a wide range of mutagenicity test
systems in vitro ; results of in vivo test systems are con-
flicting.
- Formaldehyde has been shown to form DNA-protein crosslinks in
vitro and in vivo . In vivo , this has been shown to occur at an
exposure concentration of 1.1 mg/m3.
- Formaldehyde interferes with DNA repair in human cells in vitro .
- Following inhalation exposure at levels causing cell damage, a sig-
nificant incidence of squamous cell carcinomas of the nasal cavity
was induced in 2 strains of rats.
Nasal tumours in mice have also been reported, but the incidence
was not statistically significant. There were no tumours at other
sites.
A limited number of forestomach papillomas have been reported in
rats following administration of formaldehyde in the drinking-
water.
Formaldehyde-related tumours were not observed beyond the initial
site of contact.
- Although an excess has been reported for a number of cancers, the
evidence for a causal role of formaldehyde is likely only for nasal
and nasopharyngeal cancer.
11. RECOMMENDATIONS
11.1 Recommendations for Future Research
- The absolute detection and recognition thresholds for
formaldehyde should be determined. Psychophysical function
relating the perceived irritation to the concentration of
formaldehyde should be determined. Special attention should
be given to low-concentration effects on the skin of the face
(cheeks, eyes) for both surface exposure and inhaled air
mixtures. The possible potentiation of sensory irritation by
formaldehyde at low concentrations should be further investi-
gated in mixtures of irritants with different durations of
exposure. Sensory effects, when human beings are exposed
either to air containing formaldehyde or air without formal-
dehyde, should be compared.
- The link between the perception of irritation and hyper-
reactivity and allergic reactions to formaldehyde needs
further study, in order to evaluate fully the health impli-
cations of sensory effects.
- General interaction effects of physical, environmental factors
(humidity, radiant heat, temperature, etc.) and low-concen-
tration formaldehyde exposure should be investigated with
regard to odour and sensory irritation.
- The combined effects of skin exposure to formaldehyde vapour
and inhalation exposure, on various symptoms, including sen-
sory irritation, feeling of warmth on the skin surface, qual-
ity of tactile perception, itching, tickling, and smarting of
the eyes, need investigation. Both air and contact exposure
of various body skin sites to formaldehyde at low concen-
trations should be studied for sensory effects and irritant
contact dermatitis. The interaction effects of various host
factors, such as age, psychological stress, skin disease, skin
sensitivity, genetic factors (e.g., atopic), and hormonal
balance, should be studied.
- the possible production of antibodies (IgE or other) to for-
maldehyde should be investigated. The detection of IgE anti-
bodies by RAST should be included.
- Workers, who have undergone long-term exposure to formaldehyde
should be examined for immunological effects, including clini-
cal and laboratory findings.
- Animal studies on the induction of antibodies and T-cells
specifically reacting with formaldehyde should be undertaken.
- More knowledge is needed about the factors involved in the
induction of an irritant contact dermatitis by formaldehyde,
dependent on occupational and/or other factors. Research
should be directed to the formaldehyde concentrations produc-
ing such effects as well as to the skin parameters condition-
ing the start of the irritative skin contact reaction.
- Mechanisms involved in the carcinogenicity of formaldehyde,
such as the effectiveness of mucus as a barrier, the genotoxic
consequences of DNA-protein cross-links, and the role of
tissue damage, should be studied in more detail.
- More knowledge is needed on the interactions of formaldehyde
with other air pollutants.
- Further epidemiological studies are needed including studies
on groups of people believed to be susceptible to the effects
of formaldehyde.
- There is a need for extensive follow-up studies on working
populations already investigated (maybe in excess of 20
years), because a long minimum latent period may be a feature
of the response of the human nasal epithelium to cancer-
causing agents.
- Epidemiological studies should also be re-evaluated for
mortality due to cancers of the buccal cavity and pharynx,
(human beings are not obligate nose breathers).
11.2 Recommendations for Preventive Measures
To prevent unacceptable risks, exposure to cytotoxic concentrations
of formaldehyde should be avoided.
It is recommended that consumer goods containing formaldehyde
should be labelled, in order to protect persons with a formaldehyde
allergy.
(a) Indoors:
The formaldehyde air concentration allowed in living, sleeping, and
working rooms should not be higher than 0.12 mg/m3, in order to mini-
mize the risk of repeated or continuous low concentration exposure to
formaldehyde.
(b) Occupational areas:
It is recommended that formaldehyde concentrations in the work
place air should be reduced to non-toxic concentrations. A no-
observed-adverse-effect level in monkeys was 1.2 mg/m3 (1 ppm). For
protective reasons, the concentration at the work place should be below
1.2 mg/m3 (1 ppm).
The exposure may reach a maximum of 1.2 mg/m3 (1 ppm) for 5 min
with not more than 8 peaks in one working period (up to 8 h).
(c) Cosmetics:
Formaldehyde concentrations in cosmetics (creams) that are higher
than 0.05% should be labelled and levels should be limited to 0.1% in
oral cosmetics.
The upper-level for the use of formaldehyde as a preservative in
cosmetics should be 0.2%, except in nail hardeners, which may contain
up to 5% formaldehyde.
(d) Hospitals:
1) Because of the sensitizing effect, skin contact with formaldehyde
should be avoided by wearing impermeable gloves.
2) Thermal procedures are preferred for the disinfection or steriliz-
ation of appliances and instruments. Closed containers should be
used in the disinfection of instruments using formaldehyde. Incu-
bators, scopes, and tubes should not be treated with formaldehyde.
3) Thermal laundering procedures are preferred for the disinfection of
clothing. Any "tub-disinfection" of clothing in formaldehyde sol-
ution should be exceptional. The tub must be closed with a lid. On
handling clothing, gloves (and eventually respirators) should be
worn.
4) Steam disinfecting is the method of choice for mattresses; spraying
with disinfectants is obsolete. Mattresses covered with synthetic
materials can be disinfected by wiping with formaldehyde solution,
providing ventilation is sufficient.
5) Area disinfection: Wiping or scrubbing is recommended, while
spraying with formaldehyde-containing solutions should be confined
to non-accessible places. Direct contact with the disinfectant
should be avoided by the use of gloves. Large-area disinfecting, -
laboratories etc., should be scheduled for off-work times. Suf-
ficient ventilation is mandatory.
6) Fixation of tissues in formalin baths should be performed in closed
containers and/or using an exhaust hood. If possible, tissue slices
should be washed with water, to remove superfluous formaldehyde,
before viewing them under the microscope.
12. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES
In 1983, a WHO Study Group reviewed formaldehyde in order to
recommend a health-based occupational exposure limit (WHO, 1984). The
recommendations were as follows:
"The Study Group recommends a short-term (15 minutes), health-
based occupational exposure limit for formaldehyde in air of 1.0 mg
of formaldehyde per m3 of air.
"A tentative health based exposure limit of 0.5 mg of formal-
dehyde per m3 of air is recommended as an 8-hour time-weighted
daily average during a 40-hour working week.
"In view of the reported dose-dependent carcinogenic effect of
formaldehyde in the rat, and the present inadequate epidemiological
data on the cancer risk in man, it is advisable to reduce workplace
exposure to formaldehyde to the lowest feasible level."
The carcinogenic risks for human beings were evaluated by an
International Agency for Research on Cancer ad hoc expert group in
1981. The evaluation was updated in 1987 and it was concluded that
there was limited evidence for carcinogenicity to humans and sufficient
evidence for carcinogenicity to animals (IARC, 1987).
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