INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY
ENVIRONMENTAL HEALTH CRITERIA 127
ACROLEIN
This report contains the collective views of an international group of
experts and does not necessarily represent the decisions or the stated
policy of the United Nations Environment Programme, the International
Labour Organisation, or the World Health Organization.
Published under the joint sponsorship of
the United Nations Environment Programme,
the International Labour Organisation,
and the World Health Organization
First draft prepared by Dr T. Vermeire,
National Institute of Public Health and
Environmental Protection, Bilthoven, The Netherlands
World Health Orgnization
Geneva, 1992
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WHO Library Cataloguing in Publication Data
Acrolein.
(Environmental health criteria ; 127)
1.Acrolein - adverse effects 2.Acrolein - toxicity
3.Environmental exposure 4.Environmental pollutants
I.Series
ISBN 92 4 157127 6 (LC Classification: QD 305.A6)
ISSN 0250-863X
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CONTENTS
ENVIRONMENTAL HEALTH CRITERIA FOR ACROLEIN
1. SUMMARY
2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, AND
ANALYTICAL METHODS
2.1. Identity
2.2. Physical and chemical properties
2.3. Conversion factors
2.4. Analytical methods
3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE
3.1. Natural sources
3.2. Anthropogenic sources
3.2.1. Production
3.2.1.1 Production levels and processes
3.2.1.2 Emissions
3.2.2. Uses
3.2.3. Waste disposal
3.2.4. Other sources
4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION
4.1. Transport and distribution between media
4.2. Abiotic degradation
4.2.1. Photolysis
4.2.2. Photooxidation
4.2.3. Hydration
4.3. Biotransformation
4.3.1. Biodegration
4.3.2. Bioaccumulation
5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE
5.1. Environmental levels
5.1.1. Water
5.1.2. Air
5.2. General population exposure
5.2.1. Air
5.2.2. Food
5.3. Occupational exposure
6. KINETICS AND METABOLISM
6.1. Absorption and distribution
6.2. Reaction with body components
6.2.1. Tracer-binding studies
6.2.2. Adduct formation
6.2.2.1 Interactions with sulfhydryl groups
6.2.2.2 In vitro interactions with nucleic
acids
6.3. Metabolism and excretion
7. EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST SYSTEMS
7.1. Single exposure
7.1.1. Mortality
7.1.2. Effects on the respiratory tract
7.1.3. Effects on skin and eyes
7.1.4. Systemic effects
7.1.5. Cytotoxicity in vitro
7.2. Short-term exposure
7.2.1. Continuous inhalation exposure
7.2.2. Repeated inhalation exposure
7.2.3. Repeated intraperitoneal exposure
7.3. Biochemical effects and mechanisms of toxicity
7.3.1. Protein and non-protein sulfhydryl depletion
7.3.2. Inhibition of macromolecular synthesis
7.3.3. Effects on microsomal oxidation
7.3.4. Other biochemical effects
7.4. Immunotoxicity and host resistance
7.5. Reproductive toxicity, embryotoxicity, and teratogenicity
7.6. Mutagenicity and related end-points
7.6.1. DNA damage
7.6.2. Mutation and chromosomal effects
7.6.3. Cell transformation
7.7. Carcinogenicity
7.7.1. Inhalation exposure
7.7.2. Oral exposure
7.7.3. Skin exposure
7.8. Interacting agents
8. EFFECTS ON HUMANS
8.1. Single exposure
8.1.1. Poisoning incidents
8.1.2. Controlled experiments
8.1.2.1 Vapour exposure
8.1.2.2 Dermal exposure
8.2. Long-term exposure
9. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD
9.1. Aquatic organisms
9.2. Terrestrial organisms
9.2.1. Birds
9.2.2. Plants
10. EVALUATION OF HUMAN HEALTH RISKS AND EFFECTS ON
THE ENVIRONMENT
10.1. Evaluation of human health risks
10.1.1. Exposure
10.1.2. Health effects
10.2. Evaluation of effects on the environment
11. FURTHER RESEARCH
12. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES
REFERENCES
RESUME
RESUMEN
WHO TASK GROUP ON ENVIRONMENTAL HEALTH
CRITERIA FOR ACROLEIN
Members
Dr G. Damgard-Nielsen, National Institution of Occupational Health,
Copenhagen, Denmark
Dr I. Dewhurst, Division of Toxicology and Environmental Health,
Department of Health, London, United Kingdom
Dr R. Drew, Toxicology Information Services, Safety Occupational
Health and Environmental Protection, ICI Australia, Melbourne,
Victoria, Australia
Dr B. Gilbert, Technology Development Company (CODETEC), Cidade
Universitaria, Campinas, Brazil ( Rapporteur)
Dr K. Hemminki, Institute of Occupational Health, Helsinki ( Chairman)
Dr R. Maronpot, Chemical Pathology Branch, Division of Toxicology,
Research and Testing, National Institute of Environmental Health
Sciences, Research Triangle Park, North Carolina, USA
Dr M. Noweir, Industrial Engineering Department, College of
Engineering, King Abdul Aziz University, Jeddah, Saudi Arabia
Dr M. Wallén, National Chemicals Inspectorate, Solna, Sweden
Secretariat
Ms B. Labarthe, International Register of Potentially Toxic
Chemicals, United Nations Environment Programme, Geneva,
Switzerland
Dr T. Ng, Office of Occupational Health, World Health Organization,
Switzerland
Dr G. Nordberg, International Agency for Research on Cancer, Lyon,
France
Professor F. Valic, IPCS Consultant, World Health Organization,
Geneva, Switzerland ( Responsible Officer and Secretary)a
Dr T. Vermeire, National Institute of Public Health and
Environmental Protection, Bilthoven, The Netherlands
a Vice-rector, University of Zagreb, Zagreb, Yugoslavia
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 publication. In the interest of all users of the
environmental health criteria 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.
* * *
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 or
7985850).
ENVIRONMENTAL HEALTH CRITERIA FOR ACROLEIN
A WHO Task Group on Environmental Health Criteria for Acrolein
met in Geneva from 7 to 11 May 1990. Dr M. Mercier, Manager, IPCS,
opened the meeting and welcomed the participants on behalf of the
heads of the three IPCS cooperating organizations (UNEP/ILO/WHO).
The Task Group reviewed and revised the draft monograph and made an
evaluation of the risks for human health and the environment from
exposure to acrolein.
The first draft of this monograph was prepared by Dr T.
Vermeire, National Institute of Public Health and Environmental
Protection, Bilthoven, Netherlands. Professor F. Valic was
responsible for the overall scientific content, and Dr P.G. Jenkins,
IPCS, for the technical editing.
The efforts of all who helped in the preparation and
finalization of the document are gratefully acknowledged.
ABBREVIATIONS
BOD biochemical oxygen demand
COD chemical oxygen demand
EEC European Economic Community
HPLC high-performance liquid chromatography
LOAEL lowest-observed-adverse-effect level
NAD nicotinamide adenine dinucleotide
NADPH reduced nicotinamide adenine dinucleotide phosphate
NIOSH National Institute for Occupational Safety and Health
(USA)
NOAEL no-observed-adverse-effect level
1. SUMMARY
Acrolein is a volatile highly flammable liquid with a pungent,
choking, disagreeable odour. It is a very reactive compound.
The world production of isolated acrolein was estimated to be
59 000 tonnes in 1975. A still larger amount of acrolein is
produced and consumed as an intermediate in the synthesis of acrylic
acid and its esters.
Analytical methods are available for the determination of
acrolein in various media. The minimum detection limits that have
been reported are 0.1 µg/m3 air (gas chromatography/mass
spectrometry), 0.1 µg/litre water (high-pressure liquid
chromatography), 2.8 µg/litre biological media (fluorimetry),
590 µg/kg fish (gas chromatography/mass spectrometry), and
1.4 µg/m3 exhaust gas (high-pressure liquid chromatography).
Acrolein has been detected in some plant and animal sources
including foods and beverages. The substance is primarily used as
intermediate in chemical synthesis but also as an aquatic biocide.
Emissions of acrolein may occur at sites of production or use.
Important acrolein emissions into the air arise from incomplete
combustion or pyrolysis of organic materials such as fuels,
synthetic polymers, food, and tobacco. Acrolein may make up 3-10% of
total vehicle exhaust aldehydes. Smoking one cigarette yields
3-228 µg acrolein. Acrolein is a product of photochemical oxidation
of specific organic air pollutants.
Exposure of the general population will predominantly occur via
air. Oral exposure may occur via alcoholic beverages or heated
foodstuffs.
Average acrolein levels of up to approximately 15 µg/m3 and
maximum levels of up to 32 µg/m3 have been measured in urban air.
Near industries and close to exhaust pipes, levels that are ten to
one hundred times higher may occur. Extremely high air levels in
the mg/m3 range can be found as a result of fires. In indoor air,
smoking one cigarette per m3 of room-space in 10-13 min was found
to lead to acrolein vapour concentrations of 450-840 µg/m3.
Workplace levels of over 1000 µg/m3 were reported in situations
involving the heating of organic materials, e.g., welding or heating
of organic materials.
Acrolein is degraded in the atmosphere by reaction with
hydroxyl radicals. Atmospheric residence times are about one day.
In surface water, acrolein dissipates in a few days. Acrolein has a
low soil adsorption potential. Both aerobic and anaerobic
degradation have been reported, although the toxicity of the
compound to microorganisms may prevent biodegradation. Based on the
physical and chemical properties, bioaccumulation of acrolein would
not be expected to occur.
Acrolein is very toxic to aquatic organisms. Acute EC50 and
LC50 values for bacteria, algae, crustacea, and fish are between
0.02 and 2.5 mg/litre, bacteria being the most sensitive species.
The 60-day no-observed-adverse-effect level (NOAEL) for fish has
been determined to be 0.0114 mg/litre. Effective control of aquatic
plants by acrolein has been achieved at dosages of between 4 and
26 mg/litre.h. Adverse effects on crops grown on soil irrigated by
acrolein-treated water have been observed at concentrations of
15 mg/litre or more.
In animals and humans the reactivity of acrolein effectively
confines the substance to the site of exposure, and pathological
findings are also limited to these sites. A retention of 80-85%
acrolein was found in the respiratory tract of dogs exposed to
400-600 mg/m3. Acrolein reacts directly with protein and
non-protein sulfhydryl groups and with primary and secondary amines.
It may also be metabolized to mercapturic acids, acrylic acid,
glycidaldehyde or glyceraldehyde. Evidence for the last three
metabolites has only been obtained in vitro.
Acrolein is a cytotoxic agent. In vitro cytotoxicity has
been observed at levels as low as 0.1 mg/litre. The substance is
highly toxic to experimental animals and humans following a single
exposure via different routes. The vapour is irritating to the eyes
and respiratory tract. Liquid acrolein is a corrosive substance.
The NOAEL for irritant dermatitis from ethanolic acrolein was found
to be 0.1%. Experiments with human volunteers, exposed to acrolein
vapour, show a lowest-observed-adverse-effect level (LOAEL) of
0.13 mg/m3, at which level eyes may become irritated within 5 min.
In addition, respiratory tract effects are evident from 0.7 mg/m3.
At higher single exposure levels, degeneration of the respiratory
epithelium, inflammatory sequelae, and perturbation of respiratory
function develop.
The toxicological effects from continuous inhalation exposure
at concentrations from 0.5 to 4.1 mg/m3 have been studied in rats,
dogs, guinea-pigs, and monkeys. Both respiratory tract function and
histopathological effects were seen when animals were exposed to
acrolein at levels of 0.5 mg/m3 or more for 90 days.
The toxicological effects from repeated inhalation exposure to
acrolein vapour at concentrations ranging from 0.39 mg/m3 to 11.2
mg/m3 have been studied in a variety of laboratory animals.
Exposure durations ranged from 5 days to as long as 52 weeks. In
general, body weight gain reduction, decrement of pulmonary
function, and pathological changes in nose, upper airways, and lungs
have been documented in most species exposed to concentrations of
1.6 mg/m3 or more for 8 h/day. Pathological changes include
inflammation, metaplasia, and hyperplasia of the respiratory tract.
Significant mortality has been observed following repeated exposures
to acrolein vapour at concentrations above 9.07 mg/m3. In
experimental animals acrolein has been shown to deplete tissue
glutathione and in in vitro studies, to inhibit enzymes by
reacting with sulfhydryl groups at active sites. There is limited
evidence that acrolein can depress pulmonary host defences in mice
and rats.
Acrolein can induce teratogenic and embryotoxic effects if
administered directly into the amnion. However, the fact that no
effect was found in rabbits injected intravenously with 3 mg/kg
suggests that human exposure to acrolein is unlikely to affect the
developing embryo.
Acrolein has been shown to interact with nucleic acids
in vitro and to inhibit their synthesis both in vitro and
in vivo. Without activation it induced gene mutations in bacteria
and fungi and caused sister chromatid exchanges in mammalian cells.
In all cases these effects occurred within a very narrow dose range
governed by the reactivity, volatility, and cytotoxicity of
acrolein. A dominant lethal test in mice was negative. The
available data show that acrolein is a weak mutagen to some
bacteria, fungi, and cultured mammalian cells.
In hamsters that were exposed for 52 weeks to acrolein vapour
at a level of 9.2 mg/m3 for 7 h/day and 5 days/week and were
observed for another 29 weeks, no tumours were found. When hamsters
were exposed to acrolein vapour similarly for 52 weeks, and, in
addition, to intratracheal doses of benzo[a]pyrene weekly or to
subcutaneous doses of diethylnitrosamine once every three weeks, no
clear co-carcinogenic action of acrolein was observed. Oral exposure
of rats to acrolein in drinking-water at doses of between 5 and
50 mg/kg body weight per day (5 days/week for 104-124 weeks) did not
induce tumours. In view of the limited nature of all these tests,
the data for determining the carcinogenicity of acrolein to
experimental animals are considered inadequate. In consequence, an
evaluation of the carcinogenicity of acrolein to humans is also
considered impossible.
The threshold levels of acrolein causing irritation and health
effects are 0.07 mg/m3 for odour perception, 0.13 mg/m3 for eye
irritation, 0.3 mg/m3 for nasal irritation and eye blinking, and
0.7 mg/m3 for decreased respiratory rate. As the level of
acrolein rarely exceeds 0.03 mg/m3 in urban air, it is not likely
to reach annoyance or harmful levels in normal circumstances.
In view of the high toxicity of acrolein to aquatic organisms,
the substance presents a risk to aquatic life at or near sites of
industrial discharges, spills, and biocidal use.
2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, AND
ANALYTICAL METHODS
2.1 Identity
Chemical formula: C3H4O
Chemical structure:
Relative molecular 56.06
mass:
Common name: acrolein
Common synonyms: acraldehyde, acrylaldehyde (IUPAC name),
acrylic aldehyde, propenal, prop-2-enal,
prop-2-en-1-al
Common trade Acquinite, Aqualin, Aqualine, Biocide,
names: Magnicide-H, NSC 8819, Slimicide
CAS chemical name: 2-propenal
CAS registry 107-02-8
number:
RTECS registry AS 1050000
number:
Specifications: commercial acrolein contains 95.5% or
more of the compound and, as main
impurities, water (up to 3.0% by weight)
and other carbonyl compounds (up to 1.5%
by weight), mainly propanal and acetone.
Hydroquinone is added as an inhibitor of
polymerization (0.1-0.25% by weight)
(Hess et al., 1978).
2.2 Physical and chemical properties
Acrolein is a volatile, highly flammable, lacrimatory liquid at
ordinary temperature and pressure. Its odour is described as burnt
sweet, pungent, choking, and disagreeable (Hess et al., 1978;
Hawley, 1981). The compound is highly soluble in water and in
organic solvents such as ethanol and diethylether. The extreme
reactivity of acrolein can be attributed to the conjugation of a
carbonyl group with a vinyl group within its structure. Reactions
shown by acrolein include Diels-Alder condensations, dimerization
and polymerization, additions to the carbon-carbon double bond,
carbonyl additions, oxidation, and reduction. In the absence of an
inhibitor, acrolein is subject to highly exothermic polymerization
catalysed by light and air at room temperature to an insoluble,
cross-linked solid. Highly exothermic polymerization also occurs in
the presence of traces of acids or strong bases even when an
inhibitor is present. Inhibited acrolein undergoes dimerization
above 150 °C. Some physical and chemical data on acrolein are
presented in Table 1.
Table 1. Some physical and chemical data on acrolein
Physical state mobile liquid
Colour colourless (pure) or
yellowish (commercial)
Odour perception threshold 0.07 mg/m3 a
Odour recognition threshold 0.48 mg/m3 b
Melting point -87 °C
Boiling point (at 101.3 kPa) 52.7 °C
Water solubility (at 20 °C) 206 g/litre
Log n-octanol-water partition 0.9c
coefficient
Relative density (at 20 °C) 0.8427
Relative vapour density 1.94
Vapour pressure (at 20 °C) 29.3 kPa (220 mmHg)
Flash point (open cup) -18 °C
Flash point (closed cup) -26 °C
Flammability limits 2.8-31.0% by volume
a Sinkuvene (1970) (see Table 12)
b Leonardos et al. (1969) (see Table 12)
c Experimentally derived by Veith et al. (1980)
2.3 Conversion factors
At 25 °C and 101.3 kPa (760 mmHg), 1 ppm of acrolein =
2.29 mg/m3 air and 1 mg of acrolein per m3 air = 0.44 ppm.
2.4 Analytical methods
A summary of relevant methods of sampling and analysis is
presented in Table 2.
Tejada (1986) presented data showing that the air analysis HPLC
method employing a 2,4-dinitrophenylhydrazine-coated SP cartridge
(Kuwata et al., 1983) is equivalent to that using impingers with
2,4-dinitrophenylhydrazine in acetonitrile (Lipari & Swarin, 1982).
The latter method was also evaluated in several laboratories and was
found adequate for the evaluation of the working environment (Perez
et al., 1984). Nevertheless, the separation of
2,4-dinitrophenylhydrazine derivatives of acrolein and acetone by
HPLC can present difficulties (Olson & Swarin, 1985). A highly
sensitive electrochemical detection method was found by Jacobs &
Kissinger (1982) to be suitable and was later improved by Facchini
et al. (1986).
A personal sampling device for firemen, which employs molecular
sieves, was described by Treitman et al. (1980). Other sampling
methods using solid sorbents coated with 2,4-dinitrophenylhydrazine,
as applied by Kuwata et al. (1983) for location monitoring, were
found suitable for personal sampling procedures (Andersson et al.,
1981; Rietz, 1985).
The NIOSH procedure for industrial air monitoring involves
absorption onto N-hydroxymethylpiperazine-coated XAD-2 resin and gas
chromatographic analysis of the toluene eluate (US-NIOSH, 1984).
This method has been validated by a Shell Development Company
analytical laboratory and was not revised by NIOSH in 1989.
Table 2. Sampling, preparation, and analysis of acrolein
Medium Sampling method Analytical method Detection Sample Comments Reference
limit size
air absorption in ethanolic UV spectrometry 20 µg/m3 0.02 m3 suitable for location Manita &
solution of monitoring; designed Goldberg
thiosemicar-bazide for analysis of ambient (1970)
and hydrochloric acid air; interference from
other alpha, ß-unsaturated
aldehydes
air absorption in ethanolic colorimetry 20 µg/m3 0.05 m3 suitable for location Cohen &
solution of monitoring; designed Altshuller
4-hexylresor-cinol, for analysis of ambient (1961), Katz
mercuric chloride, and and industrial air and (1977), Harke
trichloroacetic acid exhaust gas; slight et al. (1972)
interference from dienes
and alpha, ß-unsaturated
aldehydes; also suitable
for analysis of smoke
air absorption in aqueous colorimetry 20 µg/m3 0.06 m3 suitable for location Pfaffli (1982),
sodium bisulfite; monitoring; designed Katz (1977),
addition of ethanolic for analysis of ambient Ayer & Yeager
solution of and industrial air and (1982)
4-hexylresorcinol, cigarette smoke
mercuric chloride, and
trichloroacetic acid;
heating
Table 2 (contd).
Medium Sampling method Analytical method Detection Sample Comments Reference
limit size
air collection on molecular fluorimetry 2 µg/m3 0.06 m3 suitable for location Suzuki & Imai
sieve 3A and 13X; monitoring; designed (1982)
desorption by heat; for analysis of ambient
collection in water; air; interference from
reaction with aqueous croton-aldehyde and
o-aminobiphenyl-sulfuric methylvinyl ketone
acid; heating
air adsorption on Poropak N; gas chromatography < 600 0.003-0.008 suitable for personal Campbell & Moore
desorption by heat with flame ionization µg/m3 m3 monitoring (1979)
detection
air adsorption on Tenax GC gas chromatography 0.1 0.006-0.019 suitable for location Krost et al.
desorption by heat; with mass µg/m3 m3 and personal (1982)
cryofocussing spectrometric (breakthrough designed for
detection volume) analysis of ambient air
air cryogradient sampling on gas chromatography 0.1 µg/m3 0.003 m3 suitable for location Jonsson & Berg
siloxane-coated with flame monitoring; designed (1983)
chromosorb W AW; ionization and mass for analysis of ambient
desorption by heat spectrometric air
detection
air absorption into ethanol; gas chromatography 1 µg/m3 0.003-0.04 suitable for location Nishikawa et al.
reaction with aqueous with electron m3 monitoring; designed (1986)
methoxyamine capture detection for analysis of ambient
hydrochlo-ride-sodium air
acetate; bromination;
adsorption on SP-cartridge;
elution by diethyl ether
Table 2 (contd).
Medium Sampling method Analytical method Detection Sample Comments Reference
limit size
air absorption into aqueous gas chromatography 435 0.01 m3 designed for analysis Saito et al.
2,4-DNPH hydrochloride; with flame µg/m3 of exhaust gas (1983)
extraction by chloroform; ionization detection
and anthracene as
internal standard
air collection in cold trap; gas chromatography designed for analysis Rathkamp et al.
warming trap of tobacco smoke (1973)
air direct introduction gas chromatography 0.1 2 cm3 designed for analysis Richter &
g/m3 of tobacco smoke Erfuhrth (1979)
air adsorption on HPLC with UV 0.5 0.1 m3 suitable for location Kuwata et al.
2,4-DNPH-phosphoric acid detection µg/m3 monitoring; designed (1983)
coated SP-cartridge; for analysis of
elution by acetonitrile industrial and ambient
air
air absorption into solution HPLC with UV 11 0.02 m3 suitable for location Lipari & Swarin
of 2,4-DNPH-perchloric detection µg/m3 monitoring; designed (1982)
acid in acetonitrile; for analysis of exhaust
gas
air absorption into solution HPLC with 1.4 0.02 m3 suitable for location Swarin & Lipari
of 2-diphenylacetyl-1,3- fluorescence µg/m3 monitoring; designed (1983)
indandione-1-hydrazone detection for analysis of exhaust
and hydrochloric acid in gas
acetonitrile
Table 2 (contd).
Medium Sampling method Analytical method Detection Sample Comments Reference
limit size
air absorption into aqueous HPLC with 10 µg/ 1 cigarette designed for analysis Manning et al.
2,4-DNPH-hydrochloric UV detection cigarette of cigarette smoke (1983)
acid and chloroform gas phase
air absorption into gas chromatography 229 0.05 m3 suitable for US-NIOSH (1984)
2-(hydroxymethyl) with µg/m3 personal monitoring
piperidine on XAD-2; nitrogen-specific
elution by toluene detector
water addition of colorimetry 400 0.0025 slight interference Cohen &
4-hexyl-resorcinol-mercuric µg/litre litre from dienes and alpha, Altshuller (1961)
chloride solution and ß-unsaturated aldehydes
trichloroacetic acid to
sample in ethanol
water reaction with methoxylamine gas chromatography 0.4 designed for analysis Nishikawa et al.
hydrochloride-sodium with electron µg/litre of rain water (1987a)
acetate; bromination; capture detection
adsorption on SP
cartridge; elution by
diethyl ether
water reaction with 2,4-DNPH; HPLC with 29 designed for analysis Facchini et al.
with addition of electro-chemical µg/litre of fog and rain water (1986)
iso-octane detection
Table 2 (contd).
Medium Sampling method Analytical method Detection Sample Comments Reference
limit size
water low pressure distillation; HPLC with UV < 0.1 1000 ml designed for analysis Greenhoff &
cryofocussing into aqueous detection µg/litre of beer Wheeler (1981)
2,4-DNPH-hydro-chloric acid;
extraction by chloroform;
TLC and magnesia-silica-gel
column chromatography
biological reaction with aqueous fluorimetry 2.8 2 ml designed for analysis Alarcon (1968)
media m-aminophenol-hydroxyl- µg/litre of biological media
amine-hydrochloride-
hydrochloric acid;
heating
tissue homogenization; reaction HPLC with UV Boor & Ansari
with aqueous detection (1986)
2,4-DNPH-sulfuric acid;
extraction by chloroform
food ultrasonic homogenization gas chromatography 590 1000 mg designed for analysis Easley et al.
in cooled water; purging with mass µg/kg of volatile organic (1981)
by helium; trapping on spectrometric compounds in fish
Tenax GC-silica-gel-charcoal; detection
desorption by heat
3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE
3.1 Natural sources
Acrolein is reported to occur naturally, e.g., in the essential
oil extracted from the wood of oak trees (IARC, 1979), in tomatoes
(Hayase et al., 1984), and in certain other foods (section
5.2.2.).
3.2 Anthropogenic sources
3.2.1 Production
3.2.1.1 Production levels and processes
In 1975, the worldwide production of acrolein was estimated to
be 59 000 tonnes, although at this time production figures probably
only related to isolated acrolein (Hess et al., 1978). It is
mainly produced in the USA, Japan, France, and Germany. In
addition, acrolein is produced as an unisolated intermediate in the
synthesis of acrylic acid and its esters. In 1983, 216 000 to
242 000 tonnes of acrolein was reported to be used in the USA for
this purpose, amounting to 91-93% of the total production in that
country (Beauchamp et al.,1985). Formerly acrolein was produced by
vapour phase condensation of acetaldehyde and formaldehyde (Hess
et al., 1978). Although this process is now virtually obsolete,
some production via this pathway has continued in the USSR (IRPTC,
1984). Worldwide, most acrolein is now produced by the direct
catalytic oxidation of propene. Catalysts containing bismuth,
molybdenum, and other metal oxides enable a conversion of propene of
over 90% and have a high selectivity for acrolein. By-products are
acrylic acid, acetic acid, acetaldehyde, and carbon oxides (Hess
et al., 1978; Ohara et al., 1987). Another catalyst used for
this process, cuprous oxide, has a lower performance (Hess et al.,
1978; IRPTC, 1984).
3.2.1.2 Emissions
Closed-systems are used in production facilities, and releases
of acrolein to the environment are expected to be low, especially
when the compound is directly converted to acrylic acid and its
esters. The compound is emitted via exhaust fumes, process waters
and waste, and following leakage of equipment. Production losses in
the USA in 1978 were estimated to be 35 tonnes or approximately 0.1%
of the amount of isolated acrolein produced (Beauchamp et al.,
1985).
The air emission factor of acrolein in the synthesis of
acrylonitrile in the Netherlands has been reported to be 0.1-0.3 kg
per tonne of acrylonitrile (DGEP, 1988). Acrolein has also been
identified in the process streams of plants manufacturing acrylic
acid (Serth et al., 1978). The application of acrolein as a
biocide brings the chemical directly into the aquatic environment.
3.2.2 Uses
The principal use of acrolein is as an intermediate in the
synthesis of numerous chemicals, in particular acrylic acid and its
lower alkyl esters and DL-methionine, an essential amino acid used
as a feed supplement for poultry and cattle. In the USA, in 1983, 91
to 93% of the total quantity of acrolein produced was converted to
acrylic acid and its esters, and 5% to methionine (Beauchamp
et al., 1985). Other derivatives of acrolein are:
2-hydroxyadipaldehyde, 1,2,6-hexanetriol, lysine, glutaraldehyde,
tetrahydro-benzaldehyde, pentanediols, 1,4-butanediol,
tetrahydrofuran, pyridine, 3-picoline, allyl alcohol, glycerol,
quinoline, homopolymers, and copolymers (Hess et al., 1978).
Among the direct uses of acrolein, its application as a biocide
is the most significant one. Acrolein at a concentration of
6-10 mg/litre in water is used as an algicide, molluscicide, and
herbicide in recirculating process water systems, irrigation
channels, cooling water towers, and water treatment ponds (Hess
et al., 1978). About 66 tonnes of acrolein is reported to be used
annually in Australia to control submersed plants in about 4000 km
of irrigation channels (Bowmer & Sainty, 1977; Bowmer & Smith,
1984). Acrolein protects feed lines for subsurface injection of
waste water, liquid hydrocarbon fuels and oil wells against the
growth of microorganisms, and at 0.4-0.6 mg/litre it controls slime
formation in the paper industry. The substance can also be used as
a tissue fixative, warning agent in methyl chloride refrigerants,
leather tanning agent, and for the immobilization of enzymes via
polymerization, etherification of food starch, and the production of
perfumes and colloidal metals (Hess et al., 1978; IARC, 1985).
3.2.3 Waste disposal
Acrolein wastes mainly arise during production and processing
of the compound and its derivatives.
Aqueous wastes with low concentrations of acrolein are usually
neutralized with sodium hydroxide and fed to a sewage treatment
plant for biological secondary treatment. Concentrated wastes are
reprocessed whenever possible or burnt in special waste incinerators
(IRPTC, 1985).
3.2.4 Other sources
Incomplete combustion and thermal degradation (pyrolysis) of
organic substances such as fuels, tobacco, fats, synthetic and
natural polymers, and foodstuffs frequently result in the emission
of aldehydes. Reported levels are presented in section 5.1.2.
Emission rates for several of such sources are presented in Table 3.
The major sources of aldehydes in ambient air formed by
incomplete combustion and/or thermal degradation are residential
wood burning, burning of coal, oil or natural gas in power plants,
burning of fuels in automobiles, and burning of refuse and
vegetation (Lipari et al., 1984). Formaldehyde is the major
aldehyde emitted, but acrolein may make up 3 to 10 % of total
automobile exhaust aldehydes and 1 to 13% of total wood-smoke
aldehydes (Fracchia et al., 1967; Oberdorfer, 1971; Lipari
et al., 1984). Modern catalytic converters in automobiles almost
completely remove these aldehydes from exhaust gases. Acrolein may
constitute up to 7% of the aldehydes in cigarette smoke (Rickert
et al., 1980).
Aldehydes are also formed by photochemical oxidation of
hydrocarbons in the atmosphere. Leach et al. (1964) concluded
that formaldehyde and acrolein would constitute 50% and 5%,
respectively, of the total aldehyde present in irradiated diluted
car exhaust. Acrolein was considered to be mainly a product of
oxidation of 1,3-butadiene (Schuck & Renzetti, 1960; Leach et al.,
1964), but propene (Graedel et al., 1976; Takeuchi & Ibusuki,
1986), 1,3-pentadiene, 2-methyl-1,3-pentadiene (Altshuller &
Bufalini, 1965), and crotonaldehyde (IRPTC, 1984) have also been
implicated. The photooxidation of 1,3-butadiene in an irradiated
smog chamber, also containing nitrogen monoxide and air, gave rise
to the formation of acrolein (55% yield based on 1,3-buta-diene
initial concentrations). The rate of formation of acrolein was the
same as that of 1,3-butadiene consumption. (Maldotti et al.,
1980). Cancer chemotherapy patients receiving cyclo-phosphamide are
exposed to acrolein, which results from the metabolism of this drug.
Table 3. Emission rates of aldehydes
Source Total Formaldehyde Acrolein Unit Reference
aldehydes
Residential wood burning 0.6-2.3 0.089-0.708 0.021-0.132 g/kg Lipari et al. (1984)
Power plants - coal 0.002 g/kg Natusch (1978)
- oil 0.1 g/kg
- natural gas 0.2 g/kg
Automobiles - petrol 0.01-0.08 g/km Lipari et al. (1984)
0.4-2.3 0.2-1.6 0.01-0.16 g/litre Guicherit & Schulting
(1985)
8.4-63 4-38 1-2 mg/min Lies et al. (1986)
- diesel 0.021 g/km Lipari et al. (1984)
1-2 0.5-1.4 0.03-0.20 g/litre Guicherit & Schulting
(1985)
0.0080 0.0002 g/litre Smythe & Karasek (1973)
44 18 3 mg/min Lies et al. (1986)
Vegetation burning 0.003 g/kg Lipari et al. (1984)
Cigarette smoking 82-1203 3-228 µg/cigarette see section 5.2.1
Pyrolysis of flue-cured tobacco 42-82 µg/g Baker et al. (1984)
Heating in air (at up to 400 °C) of
- polyethylene up to 75 up to 20 g/kg Morikawa (1976)
- polypropylene up to 54 up to 8 g/kg
- cellulose up to 27 up to 3 g/kg
- glucose up to 18 up to 1 g/kg
- wood up to 15 up to 1 g/kg
Smouldering cellulosic materials 0.66-10.02 0.46-1.74 g/kg
Hot wire cutting (50 cm long at 215 °C)
of PVC wrapping film 27-151 ng/cut Boettner & Ball (1980)
4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION
4.1 Transport and distribution between media
Acrolein is released into the atmosphere during the production
of the compound itself and its derivatives, in industrial and
non-industrial processes involving incomplete combustion and/or
thermal degradation of organic substances, and, indirectly, by
photochemical oxidation of hydrocarbons in the atmosphere. Emissions
to water and soil occur during production of the compound itself and
its derivatives, and through biocidal use, spills, and waste
disposal (chapter 3).
Intercompartmental transport of acrolein should be limited in
view of its high reactivity, as is discussed in sections 4.2. and
4.3. Considering the high vapour pressure of acrolein, some
transfer across the water-air and soil-air boundaries can be
expected. In a laboratory experiment Bowmer et al. (1974)
explained a difference of 10% between the amount of total aldehydes
(acrolein and non-volatile degradation products, see section 4.2) in
an open tank and that in closed bottles by volatilization. It was
noted that volatilization may be greatly increased by turbulence.
Adsorption to soil, often involving probable reaction with soil
components, may impair the transfer of a compound to air or ground
water. The tendency of untreated acrolein to adsorb to soil
particles can be expressed in terms of Koc, the ratio of the
amount of chemical adsorbed (per unit weight of organic carbon) to
the concentration of the chemical in solution at equilibrium. Based
on the available empirical relationships derived for estimating
Koc, a low soil adsorption potential is expected (Lyman et al.,
1982). Experimentally, acrolein showed a limited (30% of a 0.1%
solution) adsorbability to activated carbon (Giusti et al., 1974).
4.2 Abiotic degradation
Once in the atmosphere, acrolein may photodissociate or react
with hydroxyl radicals and ozone. In water, photolysis or hydration
may occur. These processes will be discussed in the following
sections.
4.2.1 Photolysis
Acrolein shows a moderate absorption of light within the solar
spectrum at 315 nm (with a molar extinction coefficient of 26
litre/mol per cm) and therefore would be expected to be
photoreactive (Lyman et al., 1982). However, irradiation of an
acrolein-air mixture by artificial sunlight did not result in any
detectable photolysis (Maldotti et al., 1980). Irradiation of
acrolein vapour in high vacuum apparatus at 313 nm and 30-200 °C
resulted in the formation of trace amounts of ethene and carbon
oxides (Osborne et al., 1962; Coomber & Pitts, 1969).
4.2.2 Photooxidation
Experimentally determined rate constants for the pseudo first
order reaction between acrolein and hydroxyl radicals in the
atmosphere are presented in Table 4. Also shown are the atmospheric
residence times, which can be derived from the rate constants
assuming a 12-h daytime average hydroxyl radical concentration of
2 x 10-15 mol/litre (Lyman et al., 1982). The estimated
atmospheric residence time of acrolein of approximately 20 h will
decrease with increasing hydroxyl radical concentrations in more
polluted atmospheres and increase with the decline in temperature,
and consequently the rate of reaction, at higher altitudes. Other
variations will be caused by seasonal, altitudinal, diurnal, and
geographical fluctuations in the hydroxyl radical concentration.
Other potentially significant gas-phase reactions in the
atmosphere may occur between acrolein and ozone or nitrate radicals.
Experimentally determined rate constants and atmospheric residence
times for these reactions are shown in Table 4. The atmospheric
residence times were estimated assuming a 24-h average ozone
concentration of 1.6 x 10-9 mol/litre (Lyman et al., 1982) and a
12-h night-time average nitrate radical concentration of 4.0 x
10-12 mol/litre (Atkinson et al., 1987). It can be concluded
that the tropospheric removal processes for acrolein are dominated
by the reaction with hydroxyl radicals. Carbon monoxide,
formaldehyde, glycoaldehyde, ketene, and peroxypropenyl nitrate have
been identified as products of the reaction between acrolein and
hydroxyl radicals (Edney et al., 1982), and glyoxal was also
suggested to be one of the reaction products (Edney et al., 1982,
1986b).
As discussed in section 3.2.4, acrolein is also formed by the
photochemical degradation of hydrocarbons in general and
1,3-butadiene in particular. When mixtures of acrolein or
1,3-butadiene with nitrogen monoxide and air were irradiated in a
smog chamber, the time required for the half-conversion of
1,3-butadiene to acrolein was always shorter than that required for
the half conversion of acrolein. It was concluded that in a real
atmospheric environment, with continuous emissions of 1,3-butadiene,
acrolein will be continuously formed (Bignozzi et al., 1980).
Table 4. Rate constants and calculated atmospheric residence times for gas-phase reactions of acrolein.
Reactant Temperature Technique used Rate constant Atmospheric Reference
(°C) (litre/mol per sec) residence time
(h)
OH radical 25 relative rate 16 x 109 17 Maldotti et al. (1980)
25 relative rate 11.4 x 109 24 Kerr & Sheppard (1981)
23 absolute rate 20.6 x 109 13 Edney et al. (1982)
26 relative rate 11.4 x 109 24 Atkinson et al. (1983)
23 relative rate 12.3 x 109 23 Edney et al. (1986a)
O3 23 absolute rate 16.9 x 104 1029 Atkinson et al. (1981)
NO3 25 relative rate 35.5 x 104 391 Atkinson et al. (1987)
4.2.3 Hydration
Acrolein does not contain hydrolysable groups but it does react
with water in a reversible hydration reaction to 3-hydroxypropanal.
The equilibrium constant is pH independent and increases appreciably
with increasing initial acrolein concentration, presumably because
of the reversible dimerization of 3-hydroxypropanal (Hall & Stern,
1950). In more dilute solutions the equilibrium constant was found
to approach 12 at 20 °C (Pressman & Lucas, 1942; Hall & Stern,
1950), indicating that approximately 92% of acrolein is in the
hydrated form at equilibrium. This agrees well with the equilibrium
concentrations found in buffered solutions of acrolein at 21 °C
(Bowmer & Higgins, 1976).
The hydration of acrolein is a first order reaction with
respect to acrolein. The rate constants are independent of the
initial acrolein concentrations but increase with increasing acid
concentrations (Pressman & Lucas, 1942; Hall & Stern, 1950) and also
when the pH is raised from 5 to 9 (Bowmer & Higgins, 1976). In
dilute buffered solutions of acrolein in distilled water the rate
constant is 0.015 h-1 at 21 °C and pH 7, corresponding to a
half-life of 46 h. However, although in laboratory experiments an
equilibrium is reached with 8% of the original acrolein and 85% of
total aldehydes still present, these do not persist in river waters
so that other methods of dissipation must exist (Bowmer et al.,
1974; Bowmer & Higgins, 1976; see also section 4.3.1).
The dissipation of acrolein in field experiments in irrigation
channels also followed first order kinetics and was faster than
could be predicted assuming hydration alone. First order rate
constants, based on the data thought to be most reliable varied
between 0.104 and 0.208 h-1 at pH values of 7.1 to 7.5 and
temperatures of 16 to 24 °C. From these rate constants, half-lives
of between 3 and 7 h can be calculated (O'Loughlin & Bowmer, 1975;
Bowmer & Higgins, 1976; Bowmer & Sainty, 1977). The latter data
agree better than the laboratory data with the results of bioassays
with bacteria and fish, which show that aged acrolein solutions
become biocidally inactive after approximately 120 to 180 h at a pH
of 7 (Kissel et al., 1978). Apparently processes other than
hydration also contribute to acrolein dissipation, e.g., catalysis
other than acid-base catalysis, adsorption, and volatilization
(Bowmer & Higgins, 1976).
4.3 Biotransformation
4.3.1 Biodegradation
No biological degradation of acrolein was observed in two BOD5
tests with unacclimated microorganisms (Stack, 1957; Bridie et al.,
1979a) or in an anaerobic digestion test with unacclimated
acetate-enriched cultures (Chou et al., 1978). In two of these
cases this was explained by the toxicity of the test compound to
microorganisms (Stack, 1957; Chou et al., 1978). The BOD5 of
acrolein in river water containing microorganisms acclimated to
acrolein over 100 days was found to be 30% of the theoretical oxygen
demand (Stack, 1957). Applying methane fermentation in a mixed
reactor with a 20-day retention time, seeded by an acetate-enriched
culture, a 42% reduction in COD was achieved after 70-90 days of
acclimation to a final daily feed concentration of 10 g/litre (Chou
et al., 1978). In a static-culture flask-screening procedure,
acrolein (at a concentration of 5 or 10 mg/litre medium) was
completely degraded aerobically within 7 days, as shown by gas
chromatography and by determination of dissolved organic carbon and
total organic carbon (Tabak et al., 1981).
As discussed in section 4.2.3, acrolein in water is in
equilibrium with its hydration product. Bowmer & Higgins (1976)
observed rapid dissipation of this product in irrigation water after
a lag period of 100 h at acrolein levels below 2-3 mg/litre and
suggested that this could be due to biodegradation.
4.3.2 Bioaccumulation
On the basis of the high water solubility and chemical
reactivity of acrolein and its low experimentally determined log
n-octanol-water partition coefficient of 0.9 (Veith et al.,
1980), no bioaccumulation would be expected. Following the exposure
of Bluegill sunfish to 14C-labelled acrolein (13 µg/litre water)
for 28 days, the half-time for removal of radiolabel taken up by the
fish was more than 7 days (Barrows et al, 1980). Although the
accumulation of acrolein derived radioactively in this study was
described by the authors as bioaccumulation, it does not represent
bioaccumulation of acrolein per se but rather incorporation of the
radioactive carbon into tissues following the reaction of acrolein
with protein sulfhydryl groups or metabolism of absorbed acrolein
and incorporation of label into intermediary metabolites (see
chapter 6) (Barrows et al., 1980).
5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE
5.1 Environmental levels
5.1.1 Water
Concentrations of acrolein measured in various types of water
at different locations are summarized in Table 5.
5.1.2 Air
Concentrations of acrolein measured in air at different
locations are summarized in Table 6. Sources of acrolein (see
chapter 3) are reflected in the levels found.
5.2 General population exposure
5.2.1 Air
The general population can be exposed to acrolein in indoor and
outdoor air (Table 6). Levels of up to 32 µg/m3 have been
measured in outdoor urban air in Japan, Sweden, and the USA. In
addition, both smokers and non-smokers are exposed to acrolein as
the product of pyrolysis of tobacco. An extensive data base shows a
delivery of 3-228 µg of acrolein per cigarette to the smoker via the
gas-phase of mainstream smoke, the amount depending on the type of
cigarette and smoking conditions (Artho & Koch, 1969; Testa &
Joigny, 1972; Rathkamp et al., 1973; Rylander, 1973; Guerin
et al., 1974; Hoffmann et al., 1975; Richter & Erfuhrth, 1979;
Magin, 1980; Rickert et al., 1980; Manning et al., 1983; Baker
et al., 1984). The delivery of total aldehydes was found to be
82-1255 µg per cigarette (Rickert et al., 1980), consisting mainly
of acetaldehyde (Harke et al., 1972; Rathkamp et al., 1973). In
the mainstream smoke of marijuana cigarettes, 92 µg of acrolein per
cigarette was found (Hoffmann et al., 1975). Non-smokers are
mainly exposed to the side-stream smoke of tobacco products.
Smoking 1 cigarette per m3 of room-space in 10-13 min was found to
lead to acrolein levels in the gas-phase of side-stream smoke of
0.84 mg/m3 (Jermini et al., 1976), 0.59 mg/m3 (derived from
Harke et al., 1972), and 0.45 mg/m3 (derived from Hugod et al.,
1978). In one of these experiments it was observed that the
presence of people in the room reduced the acrolein levels, probably
by respiratory uptake and condensation onto hair, skin, and
clothing, (Hugod et al., 1978). Evidence has also been presented
that acrolein is associated with smoke particles. The fraction of
acrolein thus associated can be deduced to be 20-75% of the total
(Hugod et al., 1978; Ayer & Yeager, 1982).
The 30-min average acrolein levels measured in air grab-samples
from four restaurants were between 11 and 23 µg/m3, the maximum
being 41 µg/m3 (Fischer et al., 1978).
Table 5. Environmental levels of acrolein in water
Type of water Location Detection limit Levels observeda Reference
(µg/litre) (µg/litre)
Surface water USA, irrigation canal, not reported Bartley & Gangstad (1974)
point of application 100
16 km downstream 50
32 km downstream 35
64 km downstream 30
Ground water USA, water in community 0.1-3.0 nd Krill & Sonzogni (1986)
and private wells
Fog water Italy, Po valley 29 nd-120 Facchini et al. (1986)
Rain water Italy, Po valley 29 nd Facchini et al. (1986)
Rain water USA, 4 urban locations not reported nd Grosjean & Wright (1983)
USA, 1 urban location 50b
Rain water Japan, source unknown 0.04 nd (2 samples) Nishikawa et al. (1987a)
1.5-3.1 (3 samples)
a nd = not detected
b includes acetone
Table 6. Environmental levels of acrolein in air
Type of site Country Detection limit Levels observeda Reference
(µg/m3) (mg/m3)
Not defined The Netherlands 0.001 Guicherit & Schulting (1985)
Urban Los Angeles, USA 7 nd-0.025 Renzetti & Bryan (1961)
Urban Los Angeles, USA 0.002-0.032 Altshuller & McPherson (1963)
(average, 0.016)
Urban, busy road Sweden 0.1 0.012 Jonsson & Berg (1983)
Urban Japan 0.5 nd Kuwata et al. (1983)
Urban Japan 1 0.002-0.004 Nishikawa et al. (1986)
Urban, highway USSR nd-0.022 Sinkuvene (1970)
Residential, USSR
100 m from highway nd-0.013
Industrial, USSR 2.5 (max. of Plotnikova (1957)
50 m from petrochemical plant 25/25 samples)
2000 m from petrochemical plant 0.64 (max. of
21/27 samples)
1000 m from oil-seed mill USSR 0.1-0.2 Chraiber et al. (1964)
150 m from oil-seed mill USSR 0.32 Zorin (1966)
Near coal coking plant Czechoslovakia 0.004-0.009 Masek (1972)
(average, 0.007)
Table 6 (contd).
Type of site Country Detection limit Levels observeda Reference
(µg/m3) (mg/m3)
Near pitch coking plant Czechoslovakia 0.101-0.37
(average, 0.223)
Enamelled wire plants (two), USSR Vorob'eva et al. (1982)
300 m from plants 0.28-0.36
1000 m from plants 0.14-0.46
"control area" 0.001-0.23
Coffee roasting outlet USA 200 0.59 Levaggi & Feldstein (1970)
Incinerator 0.5 0.5-0.6 Kuwata et al. (1983)
Fire-fighters' personal monitors Boston, USA 1150 > 6.9 (10% of samples) Treitman et al. (1980)
in over 200 structural fires (1-litre sample) > 0.69 (50% of samples)
Enclosed space of 8 m3 containing Japan > 69 (44% of samples) Morikawa & Yanai (1986)
burning household combustibles 1370 (max)
(15% synthetics)
Enclosed space, pyrolysis of 2-5 g USA Potts et al. (1978)
of polyethylene foam in 147 litres;
chamber at 380 °C 128-355
chamber at 340 °C < 4.6
chamber at 380 °C, red oak 18.32-412.2
chamber at 245 °C, wax candles 98.47-249.61
chamber combustion of 2-5 g of 4.58-52.67
polyethylene foam
Cooking area, heating of sunflower USSR 1.1 (max) Turuk-Pchelina (1960)
oil at 160-170 °C
Table 6 (contd).
Type of site Country Detection limit Levels observeda Reference
(µg/m3) (mg/m3)
Beside exhaust of cars, 0.46-27.71 Cohen & Altshuller (1961),
unidentified fuel Seizinger & Dimitriades (1972),
Nishikawa et al. (1986, 1987b)
Beside exhaust of engines, 0.130-50.6 Sinkuvene (1970),
gasoline Saito et al. (1983)
diesel 0.58-7.2 Sinkuvene (1970),
Klochkovskii et al. (1981),
Saito et al. (1983)
Beside exhaust of cars, up to 6.1 Hoshika & Takata (1976)
gasoline Lipari & Swarin (1982)
diesel 0.5-2.1 Smythe & Karasek (1973),
Lipari & Swarin (1982),
Swarin & Lipari (1983)
ethanol 11 nd Lipari & Swarin (1982)
Near jet engine nd-0.12 Miyamoto (1986)
a max = maximum; nd = not detected
5.2.2 Food
In newly prepared beer, acrolein was found at a level of
2 µg/litre in one study (Greenhoff & Wheeler, 1981) but was not
detected in another (Bohmann, 1985). Aging can raise the level to
5 µg/litre (Greenhoff & Wheeler, 1981). Higher concentrations were
reported in another study (Diaz Marot et al, 1983). However, in
this case the eight compounds identified after a single
chromatographic procedure, except for acetaldehyde, did not include
the principal components identified after three successive
chromatographic procedures by the earlier authors (Greenhoff &
Wheeler, 1981) so that superimposition of acrolein and other
compounds may have occurred.
The identification of acrolein in wines (Sponholz, 1982)
followed adjustment of the pH to 8 and distillation procedures that
might have generated acrolein from a precursor. Similar
restrictions may apply to determinations in brandies (Rosenthaler &
Vegezzi, 1955; Postel & Adam, 1983). Heated and aged bone grease
contained an average level of 4.2 mg/kg (Maslowska & Bazylak, 1985).
Acrolein was further detected as a volatile in "peppery" rums and
whiskies (Mills et al., 1954; Lencrerot et al., 1984), apple
eau-de-vie (Subden et al., 1986), in white bread (Mulders & Dhont,
1972), cooked potatoes (Tajima et al., 1967), ripe tomatoes
(Hayase et al., 1984), vegetable oils (Snyder et al., 1985), raw
chicken breast muscle (Grey & Shrimpton, 1966), turkey meat
(Hrdlicka & Kuca, 1964), sour salted pork (Cantoni et al., 1969),
heated beef fat (Umano & Shibamoto, 1987), cooked horse mackerel
(Shimomura et al., 1971), and as a product of the thermal
degradation of amino acids (Alarcon, 1976).
5.3 Occupational exposure
Concentrations of acrolein measured at different places of work
are summarized in Table 7.
Table 7. Occupational exposure levels
Type of site Country Detection limit Levels observeda Reference
(µg/m3) (mg/m3)
Production plant for acrolein USSR 0.1-8.2 Kantemirova (1975, 1977)
and methyl mercaptopropionic
aldehyde
Plant manufacturing disposable USA 20 nd-0.07 Schutte (1977)
microscope drapes, polyethylene
sheets cut by a hot wire
Workshop where metals, coated USSR 0.11-0.57 (venting) Protsenko et al. (1973)
with anti-corrosion primers 0.73-1.04
are welded (no venting)
Workshop where metals are gas-cut 0.31-1.04
Workshop where metals (no primer) nd
are welded
Coal-coking plants Czechoslovakia 0.002-0.55 Masek (1972)
Pitch-coking plants 0.11-0.493
Rubber vulcanization plant USSR 0.44-1.5 Volkova & Bagdinov (1969)
Expresser and forepress shops USSR 2-10b Chraiber et al. (1964)
in oil seed mills
Plant producing thermoplastics Finland 20 nd Pfaffli (1982)
Engine workshops, welding Denmark 15 0.031-0.605c Rietz (1985)
a nd = not detected c 3 out of 13 samples
b It should be noted that these levels exceed normal tolerance.
6. KINETICS AND METABOLISM
6.1 Absorption and distribution
The reactivity of acrolein towards free thiol groups (section
6.3) effectively reduces the bioavailability of the substance.
Controlled experiments on systemic absorption and kinetics have not
been conducted, but there are indications that acrolein is not
highly absorbed into the system since toxicological findings are
restricted to the site of exposure (see chapters 8 & 9). The fact
that McNulty et al. (1984) saw no reduction in liver glutathione
following inhalation exposure also suggests that inhaled acrolein
does not reach the liver to any great extent (section 7.3.1).
Experiments with mongrel dogs showed a high retention of
inhaled acrolein vapour in the respiratory tract. The inhaled
vapour concentrations were measured to be between 400 and
600 mg/m3. Retention was calculated by subtracting the amount
recovered in exhaled air from the amount inhaled. The total tract
retention at different ventilation rates was 80 to 85%. Upper tract
retention, measured after severing the trachea just above the
bifurcation, was 72 to 85% and was also independent of the
ventilation rate. Lower-tract retention, measured after tracheal
cannulation, was 64 to 71% and slightly decreased as ventilation
rate increased (Egle, 1972). Evidence for systemic absorption of
acrolein from the gastrointestinal tract was reported by Draminski
et al. (1983), who identified a low level of acrolein-derived
conjugates in the urine of rats after the ingestion of a single dose
of 10 mg/kg body weight. This dose killed 50% of the animals in
this study.
6.2 Reaction with body components
6.2.1 Tracer-binding studies
The in vitro binding of 14C-labelled acrolein to protein
has been investigated using rat liver microsomes. Acrolein was
found to bind to microsomal protein in the absence of NADPH or in
the presence of both NADPH and a mixed-function oxidase inhibitor.
Incubation following the addition of free sulfhydryl-containing
compounds reduced binding by 70-90%, while the addition of lysine
reduced binding by 12%. Using gel electrophoresis-fluorography it
was shown that acrolein, incubated with a reconstituted cytochrome
P-450 system, migrated mostly with cytochrome P-450. It was
concluded that acrolein is capable of alkylating free sulfhydryl
groups in cytochrome P-450 (Marinello et al., 1984).
When rats received tritium-labelled acrolein intraperitoneally
24 h after partial hepatectomy, the percentages of total liver
radioactivity recovered in the acid-soluble fraction, lipids,
proteins, RNA, and DNA were approximately 94, 3.5, 1.2, 0.6, and
0.4%, respectively, during the first 5 h after exposure.
Distribution of label was stable for at least 24 h. Acrolein was
bound to DNA at a rate of 1 molecule per 40 000 nucleotides.
A similar DNA-binding rate was observed for the green alga
Dunaliella bioculata at a 10 times higher acrolein concentration
(Munsch et al., 1974a). In in vitro studies, labelled acrolein
was found to bind to native calf thymus DNA and other DNA polymerase
templates at rates of 0.5-1 molecule per 1000 nucleotides (Munsch
et al., 1974b). In a follow-up experiment with Dunaliella
bioculata, quantitative autoradiography and electron microscopy
showed that the preferential area of cellular fixation for acrolein
was the nucleus. This fixation was stable for at least 2 days,
while that in the plastid and cytoplasm decreased initially (Marano
& Demèstere, 1976). As no adducts were identified in these studies,
these data were considered unsuitable for evaluation.
6.2.2 Adduct formation
The findings of the tracer-binding studies (section 6.2.1) are
not surprising considering the reactivity of acrolein, which makes
the molecule a likely candidate for interactions with protein and
non-protein sulfhydryl groups and with primary and secondary amine
groups such as occur in proteins and nucleic acids. These reactions
are most likely to be initiated by nucleophilic Michael addition to
the double bond (Beauchamp et al., 1985; Shapiro et al., 1986).
Beauchamp et al. (1985) discussed extensively the interactions
with protein sulfhydryl groups and primary and secondary amine
groups.
6.2.2.1 Interactions with sulfhydryl groups
The non-enzymatic reaction between equimolar amounts of
acrolein and glutathione, cysteine or acetylcysteine in a buffered
aqueous solution proceeds rapidly to near-completion, forming stable
adducts (Esterbauer et al., 1975; Alarcon, 1976).
Acrolein-acetylcysteine and acrolein-cysteine adducts yield on
reduction S-(3-hydroxypropyl)mercapturic acid and
S-(3-hydroxypropyl)-cysteine, respectively (Alarcon, 1976). The
reaction between glutathione and acrolein may be catalysed by
glutathione S-transferase, as was shown for acrolein-diethylacetal
and crotonaldehyde (Boyland & Chasseaud, 1967). Biochemical and
toxicological investigations provide more evidence for the
interaction, either enzymatic or non-enzymatic, between acrolein and
free sulfhydryl groups. In summary, it has been observed that:
* acrolein exposure of whole organisms or tissue fractions
results in glutathione depletion (section 7.3.1);
* co-exposure of organisms to acrolein and free
sulfhydryl-containing compounds protects against the
biological effects of acrolein (sections 7.3.3, 7.3.4, and
7.5);
* acrolein can inhibit enzymes containing free sulfhydryl
groups on their active site (section 7.3);
* glutathione conjugates appear in the urine of
acrolein-dosed rats (section 6.3).
6.2.2.2 In vitro interactions with nucleic acids
Non-catalytic reactions occur between acrolein and cytidine
monophosphate (Descroix, 1972), deoxyguanosine (Hemminki et al.,
1980), and deoxyadenosine (Lutz et al., 1982). Chung et al.
(1984) have identified the nucleotides resulting from the reaction
between acrolein and deoxyguanosine or calf thymus DNA (at 37 °C and
pH 7) in phosphate buffer. The adducts identified were the 6- and
8-hydroxy derivatives of cyclic 1,N2-propano-deoxyguanosine. These
adducts were shown to be formed in a dose-dependent fashion in
Salmonella typhimurium TA100 and TA104 following exposure to
acrolein and identification of the DNA adducts by an immunoassay
(Foiles et al., 1989; see also section 7.6.2). Shapiro et al.
(1986) reported that acrolein reacts with cytosine and adenosine
derivatives (at 25 °C and pH 4.2), yielding cyclic 3,N4 adducts of
cytosine derivatives and 1,N6 adducts of adenosine derivatives.
The reaction between guanosine and acrolein yields the cyclic 1,N2
adduct (at 55 °C and pH 4).
The demonstration that acrolein can cause or enhance the
formation of complexes between DNA strands (DNA-DNA crosslinking)
and between DNA and cellular proteins (DNA-protein crosslinking) is
indirect evidence that acrolein interacts with nucleic acids. This
subject is discussed further in section 7.6.1. However, no studies
have demonstrated unequivocally the interaction of acrolein with DNA
following in vivo administration to animals.
6.3 Metabolism and excretion
Acrolein is expected to be eliminated from the body via
glutathione conjugation (section 6.2.2.1). Draminski et al.
(1983) administered acrolein in corn oil orally to Wistar rats at a
dose of 10 mg/kg body weight. The urinary metabolites identified by
gas chromatography with mass spectrometric detection were
S-carboxylethyl-mercapturic acid and its methyl ester, the latter
possibly being the result of methylation of the urine samples prior
to gas chromatography. In expired air a volatile compound was
detected by gas chromatography, which was not identified; it was
reported that its retention time did not correspond to that of
methyl acrylate, acrolein or allyl alcohol. The reduced form of
S-carboxylethyl-mercapturic acid, i.e. S-hydroxypropyl-mercapturic
acid, was identified by paper and gas chromatography as the sole
metabolite in the urine of CFE rats injected subcutaneously with a
1% solution of acrolein in arachis oil at a dose of approximately
20 mg/kg body weight (Kaye, 1973). This metabolite was collected
within 24 h and accounted for 10.5% of the total dose (uncorrected
for a recovery of 58%). These data indicate that conjugation with
glutathione may dominate the metabolism of acrolein.
Data obtained in vitro show that acrolein can also be a
substrate of liver aldehyde dehydrogenase (EC 1.2.1.5) and lung or
liver microsomal epoxidase (EC 1.14.14.1) (Patel et al., 1980).
Acrolein, at concentrations of approximately 200 mg/litre medium,
was oxidized to acrylic acid by rat liver S9 supernatant, cytosol,
and microsomes, but not by lung fractions, in the presence of NAD+
or NADP+. The reaction proceeded faster with NAD+ as cofactor
than with NADP+ and was completely inhibited by disulfiram (Patel
et al., 1980). Rikans (1987) studied the kinetics of this
reaction: mitochondrial and cytosolic rat liver fractions each
contained two aldehyde dehydrogenase activities with Km values of
22-39 mg/litre and 0.8-1.4 mg/litre. Microsomes contained a high
Km activity. Incubation of rat liver or lung microsomes in the
presence of acrolein and NADPH yielded glycidaldehyde and its
hydration product glyceraldehyde, showing involvement of microsomal
cytochrome P-450-dependent epoxidase (Patel et al., 1980).
Postulated pathways of acrolein metabolism are summarized in
Figure 1.
In a human study, the intravenous injection of 1g
cyclophosphamide resulted in the excretion of 1.5% acrolein
mercapturic acid adduct in the urine (Alarcon, 1976).
As for the fate of the primary metabolites of acrolein, it has
been proposed that acrylic acid is methylated and subsequently
conjugated to yield S-carboxyl-ethylmercapturic acid, which is a
known metabolite of methyl acrylate (Draminski et al., 1983).
However, methyl acrylate has never been reported as a metabolite of
either acrolein or acrylic acid. It seems more likely that acrylic
acid is incorporated into normal cellular metabolism via the
propionate degradative pathway (Kutzman et al., 1982; Debethizy
et al., 1987). Glycidaldehyde has been shown to be a substrate
for lung and liver cytosolic glutathione S-transferase (EC
2.5.1.18) and can also be hydrated to glyceraldehyde (Patel et al.,
1980). Glyceraldehyde can be metabolized via the glycolytic
pathways.
7. EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST SYSTEMS
7.1 Single exposure
7.1.1 Mortality
The available acute mortality data are summarized in Table 8.
Most tests for the determination of the acute toxicity of acrolein
do not comply with present standards. Nevertheless, retesting is
not justified for ethical reasons and in view of the overt high
toxicity of acrolein following inhalation or oral exposure (Hodge &
Sterner, 1943).
In addition to the data in Table 8, an oral LD95 of
11.2 mg/kg body weight for Charles River rats, observed for 24 h,
has been reported (Sprince et al., 1979). Draminski et al.
(1983) reported the deaths of 5/10 rats given 10 mg/kg body weight
in corn oil by gavage.
7.1.2 Effects on the respiratory tract
In vapour exposure tests, the effects observed in experimental
animals have almost exclusively been local effects on the
respiratory tract and eyes.
In the LC50 studies, effects on the respiratory tract were
clinically observed as nasal irritation and respiratory distress in
rats (Skog, 1950; Potts et al., 1978; Crane et al., 1986),
hamsters (Kruysse, 1971), mice, guinea-pigs, and rabbits (Salem &
Cullumbine, 1960) at exposure levels of between 25 mg/m3 for 4 h
and 95 150 mg/m3 for 3 min. Rats exposed for 10 min to
concentrations of 750 or 1000 mg/m3 suffered asphyxiation
(Catilina et al., 1966).
Histopathological investigations in experiments with
vapour-exposed rats (Skog, 1950; Catilina et al., 1966; Potts
et al., 1978; Ballantyne et al., 1989), hamsters (Kilburn &
McKenzie, 1978), guinea-pigs (Dahlgren et al., 1972; Jousserandot
et al, 1981), and rabbits (Beeley et al., 1986) revealed varying
degrees of degeneration of the respiratory epithelium consisting of
deciliation (see also in vitro work on cytotoxicity discussed in
7.1.5), exfoliation, necrosis, mucus secretion, and vacuolization.
Also observed were acute inflammatory changes consisting of
infiltration of white blood cells into the mucosa, hyperaemia,
haemorrhages, and intercellular oedema. Proliferative changes of
the respiratory epithelium, in the form of early stratification and
hyperplasia, were observed in hamsters 96 h after exposure to
13.7 mg/m3 for 4 h (Kilburn & McKenzie, 1978).
Table 8. Acute mortality caused by acrolein
Species/strain Sex Route of exposure Observation LD (mg/kg bw) Reference
period (days) or LC50 (mg/m3)a
Rat (Wistar) male inhalation (10 min) 8 750 Catilina et al. (1966)b
Rat (Wistar) not reported oral 14 46 (39-56) Smyth et al. (1951)g
Rat (unspecified not inhalation (30 min) 21 300 Skog (1950)b,c
strain) reported
Rat (Sprague-Dawley) male inhalation (30 min) 14 95-217 Potts et al. (1978)d
Rat (Sprague-Dawley) male and inhalation (1 h) 14 65 (60-68) Ballantyne et al. (1989)
female inhalation (4 h) 14 20.8 (17.5-24.8)
Rat (Sherman) male and inhalation (4 h) 14 18 Carpenter et al. (1949)b,e
female
Hamster (Syrian golden) male and inhalation (4 h) 14 58 (54-62) Kruysse (1971)
female
Table 8 (contd)
Species/strain Sex Route of exposure Observation LD (mg/kg bw) Reference
period (days) or LC50 (mg/m3)a
Mouse (unspecified male inhalation (6 h) 1 151 Philippin et al. (1970)f
strain)
Mouse (NMRI) not reported intraperitoneal 6 7 Warholm et al. (1984)g
a Where available, 95% confidence limits are given in parentheses.
b Determination of acrolein levels was not reported.
c No mortality at 100 mg/m3, 100% mortality at 700 mg/m3.
d Approximate value: no mortality at 33 mg/m3, 1/7 and 7/7 died at 95 and 217 mg/m3, respectively.
e Approximate value: 2-4/6 died.
f No mortality at 71 mg/m3, 100% mortality at 273 mg/m3.
g The vehicle was water.
Functional changes in the respiratory system following acrolein
vapour exposure have been investigated in guinea-pigs and mice. A
rapidly reversible increase in respiratory rate was observed in
intact guinea-pigs during exposure to 39 mg/m3 for 60 min (Davis
et al., 1967) and to 0.8 mg/m3 or more for 2 h (Murphy et al.,
1963) followed by a decrease in respiratory rate and an increase in
tidal volume. No changes in pulmonary compliance were reported.
Davis et al. (1967) did not observe these effects in
tracheotomized animals and concluded that they were caused by reflex
stimulation of upper airway receptors and not by
bronchoconstriction. Murphy et al. (1963), observing that
anticholinergic bronchodilators, aminophylline and isoproterenol,
but not antihistaminics, reduced the acrolein-induced increase in
respiratory resistance, concluded that acrolein caused
bronchoconstriction mediated through reflex cholinergic stimulation.
In another experiment, an increase in respiratory resistance was
also observed in anaesthetized, tracheotomized guinea-pigs with
transected medulla during exposure to 43 mg/m3 for up to 5 min
(Guillerm et al., 1967b). The effect was not reversed by atropine.
It was concluded by the authors that acrolein did not cause
bronchoconstriction via reflex stimulation, but probably via
histamine release. When anaesthetized mice were exposed to 300 or
600 mg/m3 for 5 min via a tracheal cannula, respiratory
resistance, respiratory rate, and tidal volume decreased and
pulmonary compliance increased at an unspecified time after exposure
(Watanabe & Aviado, 1974).
The concentration that produces a 50% decrease in respiratory
rate (RD50) as a result of reflex stimulation of trigeminal nerve
endings in the nasal mucosa (sensory irritation) has been used as an
index of upper respiratory tract irritation. This effect reduces
the penetration of noxious chemicals into the lower respiratory
tract. The rate of respiration was measured in a body
plethysmograph, only the animals' heads being exposed to the
acrolein vapour. Depending on the strain, RD50 values for mice
ranged from 2.4 to 6.6 mg/m3 (Kane & Alarie, 1977; Nielsen
et al., 1984; Steinhagen & Barrow, 1984). In rats a RD50 of
13.7 mg/m3 was found (Babiuk et al., 1985).
7.1.3 Effects on skin and eyes
Animal skin irritation tests have not been performed and skin
irritation has not been mentioned as an effect in the acute
inhalation tests reported.
One special in vivo eye irritation test involved
vapour-exposed and control rabbits. At analysed concentrations of
acrolein (method not specified) between 4.3 and 5.9 mg/m3,
maintained over 4 h, slight chemosis was observed but no iritis
(Mettier et al., 1960). Eye irritation was observed clinically in
rodents in several acute inhalation tests, but was not graded (Skog,
1950; Salem & Cullumbine, 1960; Kruysse, 1971; Potts et al.,
1978).
7.1.4 Systemic effects
With respect to systemic effects, most studies have been
performed at concentrations far above the lethal dose. When rats
were exposed to concentrations of acrolein between 1214 and
95 150 mg/m3 during various periods of time, incapacitation,
indicated by the inability to walk in a rotating cage, and
convulsions were observed after 2.8 min at the highest concentration
and after 27 to 34 min at the lowest concentration. These effects
were followed by death after several minutes. Cyanosis of the
extremities and agitation were observed at levels of 22 900 mg/m3
or more (Crane et al., 1986).
The effects of acrolein on the cardiovascular system were
investigated by Egle & Hudgins (1974). Rats anaesthetized by sodium
pentobarbital and exposed only via the mouth and nose to
concentrations between 10 and 5000 mg/m3 for 1 min showed an
increase in blood pressure at all exposure levels. The heart rate
was increased at concentrations from 50 mg/m3 to 500 mg/m3 but
decreased at 2500 and 5000 mg/m3. Intravenous experiments
suggested that increased blood pressor responses resulted from the
release of catecholamines from sympathetic nerve endings and from
the adrenal medulla and that the decreased heart rate effect was
mediated by the vagus nerve (Egle & Hudgins, 1974).
In an acute oral test with rats exposed at 11.2 mg/kg body
weight, decreased reflexes, body sag, poor body tone, lethargy,
stupor, and tremors were observed, as well as respiratory distress
(Sprince et al., 1979).
Because acrolein was shown to induce acute cytotoxicity of the
rat urinary bladder mucosa when instilled directly into the bladder
lumen (Chaviano et al., 1985), this end-point was investigated
in vivo. Two days after a single oral or intraperitoneal dose of
25 mg/kg body weight to ten rats per group, focal simple hyperplasia
of the urinary bladder was detected in the three surviving rats
dosed intraperitoneally. None of the orally exposed rats showed
this effect, but all exhibited severe erosive haemorrhagic
gastritis. Both orally and intraperitoneally exposed rats showed
eosinophilic degeneration of hepatocytes. No abnormalities were
observed in sections of lungs, kidneys, and spleen. Acrolein was
also administered intraperitoneally at single doses of 0.5, 1, 2, 4,
or 6 mg/kg body weight. Proliferation of the bladder mucosa was
evaluated autoradiographically by measuring [3H-methyl]thymidine
incorporation in exposed versus control rats 5 days after the
intraperitoneal injection of acrolein and was found to be increased
nearly two-fold at the highest dose. Body weight gain was decreased
at the two highest doses. Histopathological evaluation of the liver
and urinary bladder did not reveal abnormalities (Sakata et al.,
1989).
7.1.5 Cytotoxicity in vitro
As shown in Table 9, mammalian cell viability is affected by
acrolein in vitro at nominal concentrations of 0.1 mg/litre or
more (not corrected for interaction with culture medium components
or volatilization). The concentration at which formaldehyde
exhibited a similar degree of cytotoxicity was about 6 to 100 times
higher (Holmberg & Malmfors, 1974; Pilotti et al., 1975; Koerker
et al., 1976; Krokan et al., 1985).
Acrolein is a known inhibitor of respiratory tract ciliary
movement in vitro. After a 20-min exposure to an acrolein
concentration of 34-46 mg/m3, the ciliary beating frequency of
excised sheep trachea decreased by 30% (Guillerm et al., 1967a).
Exposure to 13 mg/m3 for 1 h is the greatest exposure that does
not stop ciliary activity in excised rabbit trachea (Dalhamn &
Rosengren, 1971). The no-observed-effect-level for longer exposure
periods would be expected to be lower than 13 mg/m3. Other
in vitro investigations into the inhibition of ciliary movement by
acrolein were reviewed by Izard & Libermann (1978).
7.2 Short-term exposure
7.2.1 Continuous inhalation exposure
In two subchronic inhalation studies with rats, changes in
weight gain, longevity, behaviour, and several physiological
parameters were reported (Gusev et al., 1966; Sinkuvene, 1970).
Unfortunately, the reports did not give sufficient details on the
exposure conditions and protocols and the studies are thus of
limited value in evaluating the toxicological properties of
acrolein.
Table 9. In vitro cytotoxicity of acrolein
Cell type Exposure Effect Concentration Reference
period (h) (mg/litre medium)
Rat cardiac fibroblasts/myocytes 4 increased lactate Toraason et al. (1989)
dehydrogenase release > 2.8
Rat cardiac myocytes 2 abolished myocine beat > 2.8
dehydrogenase
4 decreased ATP levels > 0.56
Mouse Ehrlich Landschutz 5 92% survivala 1 Holmberg & Malmfors (1974)
Diploid ascites tumour cells 5 53% survivala 5
Mouse B P8 ascites sarcoma cells 48 20% growth rate inhibition 0.6 Pilotti et al. (1975)
48 94% growth rate inhibition 5.6
Mouse C1300 neuroblastoma cells 24 50% survivala 1.7 Koerker et al. (1976)
Mouse L 1210 leukaemia cells 1 70-80% survivala 1.1 Wrabetz et al. (1980)
1 < 15% survivala 2.8
Chinese hamster ovary cells 5 100% mitotis inhibition 0.6 Au et al. (1980)
Adult human bronchial 1 92% colony-forming efficiency 0.06 Krokan et al. (1985)
fibro-blasts 1 45% colony-forming efficiency 0.2
Table 9 (contd).
Cell type Exposure Effect Concentration Reference
period (h) (mg/litre medium)
Adult human lymphocytes 48 decreased replicative index 0.6 Wilmer et al. (1986)
48 100% mitosis inhibition 2.2
Human K562 chromic myeloid 1 marked reduction in > 0.3 Crook et al. (1986a,b)
leukaemia cells colony-forming ability
Human bronchial epithelial cells 1 20% colony-forming efficiency 0.06 Grafström et al. (1988)
1 50% colony-forming efficiency 0.06-0.17
1 50% survivala 0.34
3 clonal growth rate inhibition > 0.17
3 increase in cross-linkage
envelope formation > 0.06
3 decreased plasminogen
activator activity > 0.56
Human fibroblasts 5 63% cell count reduction < 0.017 Curren et al. (1988)
DNA-repair deficient human
fibroblasts 5 63% cell count reduction 0.045
a measured as dye exclusion
Groups of 7 or 8 Sprague-Dawley rats of both sexes, 7 or 8
Princeton or Hartley-derived guinea-pigs of both sexes, 2 male
pure-bred Beagle dogs, and 9 male squirrel-monkeys were exposed to a
vapourized acrolein-ethanol-water mixture for 90 days (Lyon et al.,
1970). The measured acrolein concentrations were 0, 0.5 (two groups
for each species), 2.3, and 4.1 mg/m3 and the ethanol
concentrations were below 18.7 mg/m3. Pathological investigations
did not include weighing of tissues and organs or examination of the
tracheas at the lowest exposure level. There was no
treatment-related mortality. One monkey died at 0.5 mg/m3 and one
at 2.3 mg/m3 due to accidental infections. Body weight gain
reduction was only found in rats at 2.3 and 4.1 mg/m3.
Clinically, ocular discharge and salivation were observed in dogs at
2.3 and 4.1 mg/m3 and in monkeys at 4.1 mg/m3. Monkeys kept
their eyes closed at 2.3 mg/m3. No adverse effects on
haematological or biochemical parameters were observed in any of the
animals. At necropsy, occasional pulmonary haemorrhage and focal
necrosis in the liver were found in three rats at 2.3 mg/m3.
Pulmonary inflammation and occasional focal liver necrosis were also
observed in guinea-pigs at this concentration. Sections of lung
from two of the four dogs exposed at 0.5 mg/m3 revealed focal
vacuolization, hyperaemia, and increased secretion of bronchiolar
epithelial cells, slight bronchoconstriction, and moderate
emphysema. At 2.3 mg/m3, focal inflammatory reactions involved
lung, kidney, and liver. Bronchiolitis and early broncho-pneumonia
were seen in one dog. At 4.1 mg/m3, both dogs had confluent
bronchopneumonia. All nine monkeys at 4.1 mg/m3 showed squamous
metaplasia and six of them showed basal cell hyperplasia in the
trachea. None of the species revealed other treatment-related
changes (Lyon et al., 1970).
Bouley et al. (1975) exposed a total of 173 male SPF-OFA rats
to a measured acrolein vapour concentration of 1.26 mg/m3 for a
period of 15 to 180 days and used control groups of equal size. No
mortality occurred. Sneezing was observed from day 7 to day 21 in
the treated animals, and body weight gain and food consumption were
reduced. There was an increase in relative lung weight in rats
killed on day 77 but not in rats killed on days 15 or 32. The
relative liver weight was decreased at day 15 but not thereafter,
and the number of alveolar macrophages was decreased at days 10 and
26 but not at days 60 or 180. When groups of 16 rats were infected
by one LD50 dose of airborne Salmonella enteriditis on day 18 or
day 63, mortality increased from 53% in controls to 94% in the
exposed rats infected on day 18. No changes were observed in
biochemical parameters, including the amount of liver DNA per mg of
protein in a group of partially hepatectomized rats, or in the
response of spleen lymphocytes to phytohaemagglutinin in rats
exposed for 39 to 57 days. Other end-points were not investigated.
7.2.2 Repeated inhalation exposure
Lyon et al. (1970) exposed groups of rats, guinea-pigs, dogs,
and monkeys to acrolein vapour at concentrations of 0, 1.6. and
8.5 mg/m3 for 8 h per day and 5 days per week over 6 weeks. With
the exception of the exposure levels, period, and frequency, the
protocol was the same as that for the continuous inhalation exposure
described in section 7.2.1. Two deaths occurred among the nine
monkeys at 8.5 mg/m3. There was body weight gain reduction in
rats and body weight loss (not statistically significant) in monkeys
at 8.5 mg/m3. Clinically, eye irritation and salivation were
observed in dogs and monkeys and difficult breathing in dogs at
8.5 mg/m3. No adverse effects on haematological or biochemical
parameters were observed in any of the animals. At necropsy,
sections of lung from all animals exposed to 1.6 mg/m3 showed
chronic inflammatory changes. Additionally, some showed emphysema.
At 8.5 mg/m3, squamous metaplasia and basal cell hyperplasia were
observed in the trachea of both dogs and monkeys. In addition,
bronchopneumonia was noted in dogs and necrotizing bronchitis and
bronchiolitis in monkeys. Focal calcification of the tubular
epithelium was noted in the kidneys of rats and monkeys at
8.5 mg/m3.
Groups of male Sprague-Dawley rats were also exposed to
acrolein vapour at measured concentrations of 0, 0.39, 2.45, and
6.82 mg/m3 for 6 h per day and 5 days per week over 3 weeks (Leach
et al., 1987). Subgroups were used for immunological
investigations (section 7.4) and for histopathological examination
of nasal turbinates and lungs. Body weight gain was depressed from
week 1 up to the end of the exposure period at 6.82 mg/m3.
Absolute, but not relative, spleen weight was reduced at this
exposure level. There were no histological effects on the lungs,
but the respiratory epithelium of the nasal turbinates showed
exfoliation, erosion, and necrosis, as well as dysplasia and
squamous metaplasia at 6.82 mg/m3. In addition, the mucous
membrane covering the septum and lining the floor of the cavity
showed hyperplasia and dysplasia (Leach et al., 1987).
Another experiment involved Dahl rats of two lines, one
susceptible (DS) and one resistant (DR) to salt-induced hypertension
(Kutzman et al., 1984). Groups of 10 female rats of each line were
exposed to measured acrolein concentrations of 0, 0.89, 3.21, and
9.07 mg/m3 for 6 h per day and 5 days per week over 61-63 days.
One week after the exposure, survivors were killed for pathological
and compositional analysis of the lung following behavioural and
clinical chemistry testing. At 9.07 mg/m3, all DS rats died
within 11 days and 4 DR rats died within the exposure period.
Reduced body weights were measured in the surviving DR rats during
the first 3 weeks, followed by an almost normal body weight gain.
Biochemical changes were found in DR rats at 9.07 mg/m3 and
included increases in lung hydroxyproline and elastin, serum
phosphorus, and in the activities of serum alkaline phosphatase,
alanine aminotransferase (EC 2.6.1.2), and aspartate
aminotransferase (EC 2