IPCS INCHEM HomeAcrylamide
ACRYLAMIDE
International Programme on Chemical Safety
Poisons Information Monograph 652
Chemical
1. NAME
1.1 Substance
Acrylamide
1.2 Group
Amide
1.3 Synonyms
2-Propenamide;
Acrylic acid amide;
Acrylic amide;
Acrylamide monomer;
Akrylamid;
Ethylene carboxamide;
Propenamide;
Propeneamide;
Propenoic acid amide.
1.4 Identification numbers
1.4.1 CAS number
79-06-1
1.4.2 Other numbers
DOT: UN 2074
RCRA Waste number: U007
RTECS registry number: AS 33250000
1.5 Main brand names, main trade names
USA: AAM; Optimum; Amresco Acryl-40; Optimum; Acrylage 1
1.6 Main manufacturers, main importers
American Cyanamid Company
Headquarters: 1 Cyanamid Plaza, Wayne, NJ
07470.
Production facilities: Avondale, LA 70094.
Linden, NJ 07037.
Botlek, The Netherlands.
Dow Chemical USA
Headquarters: 2020 Dow Center, Midland, MI
48674.
Production facility: Main Street, Midland, MI
48667.
Nalco Chemical Co.
Headquarters: One Nalco Center,
Naperville, IL 60566-1024.
Production facility: Garyville, LA 70051.
BF Goodrich Co. 6100 Oak Tree Blvd,
Cleveland, OH
Tel: (216) 447-7802,
Cosan Chemical Corp. 400 14th St, Carlstadt, NJ
07072
Tel (201) 460-9300.
2. SUMMARY
2.1 Main risks and target organs
Acrylamide is a potent neurotoxin affecting both the
central and peripheral nervous systems. The magnitude of the
toxic effect depends on the duration of exposure and the
total dose.
Only the acrylamide monomer is toxic. Acrylamide polymers
are non-toxic.
2.2 Summary of clinical effects
Acute ingestion
Behavioural disturbance.
Auditory and visual hallucinations.
Depressed level of consciousness.
Seizures.
Hypotension.
Adult respiratory distress syndrome.
Delayed peripheral neuropathy.
Chronic Occupational exposure
Contact dermatitis.
Excessive sweating, especially of extremities.
Fatigue.
Weight loss with normal appetite.
Neurobehavioural changes.
Truncal ataxia.
Signs and symptoms of motor and sensory peripheral
neuropathy.
2.3 Diagnosis
Acute
The initial diagnosis is based on a history of ingestion of
even a few grams of acrylamide crystal. The patient who
presents asymptomatic may develop severe symptoms with a
delay of many hours. The diagnosis should be considered in
an individual with access to acrylamide (for example a
laboratory worker) who develops a central nervous system,
cardiovascular and respiratory disturbance over a period of
hours.
Chronic
Acrylamide intoxication is a clinical diagnosis and should be
strongly suspected whenever truncal ataxia with peripheral
neuropathy is detected in an acrylamide-exposed worker. The
presence of excessive sweating and redness and peeling of the
skin of the hands and feet makes the diagnosis even more
likely.
Laboratory studies are unhelpful.
Evidence of peripheral neuropathy on nerve conduction studies
supports the diagnosis of acrylamide neurotoxicity. Normal
studies do not exclude the diagnosis.
2.4 First-aid measures and management principles
Acute oral, dermal or inhalational exposures are
initially managed by appropriate decontamination. Victims of
acute exposure should be followed for signs or symptoms of
toxicity.
Established toxicity following occupational exposure is
managed by prevention of further exposure. No specific
therapy exists.
Prevention of toxicity from repeated occupational exposure is
most important. This is achieved by minimising exposure
amongst workers handling the chemical.
3. PHYSICO-CHEMICAL PROPERTIES
3.1 Origin of the substance
All acrylamide in the environment is synthetic.
Commercial production commenced in 1954.
Acrylamide, a vinyl monomer, is formed from the hydration of
acrylonitrile by sulfuric acid monohydrate at 90 to 100ーC.
From the resulting sulfate solution, acrylamide is extracted
by neutralization with ammonia and subsequent cooling to
isolate the crystalline monomer.
Copper salts are added to the solution to suppress formation
of by-products of polyacrylamide and acrylic acid.
Alternatively, acrylamide can be produced by direct catalytic
conversion in which an aqueous solution of acrylonitrile is
passed over a fixed bed of copper or copper-metal admixtures
at 25 to 200ーC (Macwilliam, 1978).
3.2 Chemical structure
Structural names: 2-Propenamide
Molecular formula: C3H5NO
Molecular weight: 71.08
3.3 Physical properties
3.3.1 Colour
White.
3.3.2 State/Form
Crystalline solid at room temperature.
Liquid form is 40% (weight/volume) solution in
specially deionized water.
3.3.3 Description
Melting point: 84.5ーC
Vapour pressure: 0.009 kPa at 25ーC
0.004 kPa at 40ーC
0.09 kPa at 50ーC
Boiling point: 87ーC at 0.267 kPa
103ーC at 0.667 kPa
125ーC at 3.33 kPa
Heat of polymerization: 19.8 kcal/mole
Density: 1.122 g/cm3 at 30ーC
Solubility in g/L solvent at 30ーC:
Acetone 631
Benzene 3.46
Chloroform 26.6
Ethanol 862
Ethyl acetate 126
n-heptane 0.068
Methanol 1550
Water 2155
Conversion factor: 1 ppm acrylamide in air = 5
mg/m3
(Budavari et al., 1989)
3.4 Other characteristics
Odourless.
Readily polymerizes if heated to melting point or if exposed
to ultraviolet radiation (Budavari et al., 1989).
4. USES/CIRCUMSTANCES OF POISONING
4.1 Uses
4.1.1 Uses
4.1.2 Description
Acrylamide is used for the production of high
molecular weight polyacrylamides which are modified to
produce different physical and chemical properties
suited to a wide variety of industrial
applications.
Large quantities of polyacrylamide gel are produced on
site for use as a grouting agent, particularly for the
sealing of mineshafts in the mining industry.
Polyacrylamides are used in large quantities as
flocculators (substances that aid the separation of
suspended solids from aqueous systems) in the
following industries:
Water treatment.
Pulp and paper processing.
Crude oil production processes.
Mineral ore processing.
Concrete processing.
Soil and sand treatment.
Smaller quantities of polyacrylamides are used in the
following applications:
Cosmetic additives.
Permanent press fabrics.
Electrophoresis, molecular biology
applications.
Photographic emulsions.
Adhesive manufacture.
Food processing.
4.2 High risk circumstance of poisoning
Only the acrylamide monomer is neurotoxic. Those
workers involved in the synthesis of acrylamide monomer or
polymerization processes are at risk of exposure.
4.3 Occupationally exposed populations
Any workers required to handle acrylamide monomer
especially in industries where large quantities are used.
Virtually all reported cases have occurred in the following
groups of workers:
Acrylamide monomer production facility workers.
Flocculator production workers.
Mineworkers involved in grouting operations.
5. ROUTES OF ENTRY
5.1 Oral
Well absorbed. Unusual route in human exposure.
5.2 Inhalation
Well absorbed. Important route in occupational
exposure.
5.3 Dermal
Well absorbed. Important route in occupational
exposure.
5.4 Eye
No data available.
5.5 Parenteral
Not reported in humans. Acrylamide is well absorbed
following intravenous, intramuscular, intraperitoneal and
subcutaneous administration in animals.
5.6 Others
Not reported in humans. Well absorbed following mucosal
application in animal experiments.
6. KINETICS
6.1 Absorption by route of exposure
Acrylamide is rapidly and well absorbed by intravenous,
intraperitoneal, subcutaneous, intramuscular, oral,
transmucosal and dermal routes (Kuperman, 1958). In rats,
absorption of acrylamide following oral administration is
virtually complete. However, only about 25% of a dose
applied to the skin is absorbed over the subsequent 24 hours
(Dearfield et al., 1988). [Note: all data derived from
animal studies].
6.2 Distribution by route of exposure
Following absorption, acrylamide is rapidly distributed
throughout the total body water. Tissue distribution is not
significantly affected by dose or route of administration.
Highest concentrations are found in red blood cells. Despite
the prominence of neurological effects, acrylamide is not
concentrated in nervous system tissues (Miller et al.,
1982).
Acrylamide readily crosses the placenta (Edwards, 1976).
[Note: all data derived from animal studies].
6.3 Biological half-life by route of exposure
In blood, acrylamide has a half-life of approximately 2
hours. In tissues, total acrylamide (parent compound and
metabolites) exhibits biphasic elimination with an initial
half-life of approximately 5 hours and a terminal half life
of 8 days (Edwards, 1975; Miller et al., 1982).
Acrylamide does not accumulate in the body. [Note: all data
derived from animal studies].
6.4 Metabolism
Acrylamide undergoes biotransformation by conjugation
with glutathione (Edwards, 1975; Miller et al., 1982) or
reduction by microsomal cytochrome P-450 (Kaplan et al.,
1973) with glutathione conjugation probably being the major
route of detoxification. The metabolites are non-toxic
(Edwards, 1975). [Note: all data derived from animal
studies].
6.5 Elimination by route of exposure
Greater than 90% of absorbed acrylamide is excreted in
the urine as metabolites. Less than 2% is excreted as
unchanged acrylamide. Smaller amounts are excreted in the
bile and faeces (Miller et al., 1982).
Approximately 60% of an administered dose appears in the
urine within 24 hours (Miller et al., 1982). [Note: all data
derived from animal studies].
7. TOXICOLOGY
7.1 Mode of Action
Exposure to acrylamide produces a distal axonopathy
(also known as "dying-back" neuropathy) in both humans and
experimental animals. Both central nervous system (CNS) and
peripheral nervous system (PNS) neurons are affected although
CNS damage appears to require exposure to much higher
concentrations. There is some potential for regeneration of
PNS neurons but damage to CNS neurons is permanent.
The mechanism by which this distal axonopathy is produced
remains unknown although several theories have been advanced,
all supported by some experimental evidence. It appears that
acrylamide interferes with axonal retrograde transport
mechanisms essential for the survival of the axon.
Acrylamide has been shown to bind to DNA (Carlson & Weaver,
1985) which may result in the production of unsound
structural proteins essential for axonal function. It has
also been postulated that acrylamide enters the neuron at the
neuromuscular junction by pinocytosis and then binds to
tubulin sulfhydryl goups in the axon resulting in disassembly
of microtubules and consequent disruption of retrograde
transport (Smith & Oehme, 1991). Other mechanistic theories
include deregulation of axonal and/or Schwann cell elements
and water (LoPachin et al., 1992a, b) and altered neuronal
calcium homeostasis interfering with calmodulin-dependent
enzymes and phosphorylation of cytoskeletal proteins (Xiwen
et al., 1992; Reagan et al., 1994).
Acrylamide may mediate some of its CNS effects by altering
neurotransmitter concentration and function. Acrylamide has
been shown to decrease CNS concentrations of noradrenalin,
dopamine and 5-hydroxytryptamine and also appears to alter
responsiveness to dopamine by affecting postsynaptic dopamine
receptor affinity and density (Tilson, 1981).
7.2 Toxicity
7.2.1 Human data
7.2.1.1 Adults
No relevant data.
7.2.1.2 Children
No relevant data.
7.2.2 Relevant animal data
Numerous investigators have looked at
dose-response and dose-effect relationships in a
variety of animal models. There do not appear to be
significant differences between mammalian species
studied.
The LD50 for a single dose of oral acrylamide in rats,
guinea pigs and rabbits is 150-180 mg/kg (McCollister
et al., 1964).
Evidence of neurological effect has been observed
following single oral doses of 126 mg/kg in rats and
rabbits (McCollister et al., 1964) and 100 mg/kg in
dogs (Kuperman, 1958).
Using chronic dosing schedules, it has been observed
that cumulative oral doses of 500-600 mg/kg using
daily doses of 25-50 mg/kg/day are required to produce
ataxia in rats, dogs and baboons (McCollister et al.,
1964; Thomann et al., 1974; Hopkins, 1970). Smaller
daily doses do not produce a clinical effect until a
larger cumulative dose is attained; Fullerton &
Barnes (1966) observed that administration of
acrylamide at daily doses of 6 to 9 mg/kg did not
produce evidence of neurotoxicity in rats until a
cumulative dose of 1200 to 1800 mg/kg was
attained.
McCollister et al. (1964) observed that doses of up
to 3 mg/kg/day for 90 days administered to rats did
not result in adverse effects. Spencer et al. (1979)
reported that Rhesus monkeys fed up to 2 mg/kg/day did
not show any adverse clinical effects at 325
days.
7.2.3 Relevant in vitro data
No relevant data.
7.2.4 Workplace standards
Occupational Safety and Health Act (OSHA) (USA)
air contaminant standard, time-weighted average: 0.03
mg/m3 (skin)
American Conference of Government Industrial
Hygienists (ACGIH), threshold limit value (TLV): 0.03
mg/m3 (skin)
National Institute for Occupational Safety and Health
(NIOSH) (USA), time-weighted average: 0.3 mg/m3
Designation "(skin)" following air concentration
values indicates that the compound may be absorbed
through the skin and that, even though the air
concentration may be below standard, significant
additional exposure through the skin is possible
(Lewis, 1993).
7.2.5 Acceptable daily intake (ADI) and other guideline
levels
Not relevant.
7.3 Carcinogenicity
Chronic acrylamide exposure has been associated with
increased incidence of mesothelioma and cancers of the
central nervous system, thyroid gland, other endocrine
glands, mammary glands and reproductive tracts in rats
(Johnson et al., 1986) and with lung adenomas in mice (Bull
et al., 1984).
Epidemiologic studies of workers exposed to acrylamide have
failed to demonstrate any relation between exposure to
acrylamide and either overall incidence of malignancy or
incidence of specific cancers (Sobel et al., 1986; Collins et
al., 1989).
7.4 Teratogenicity
Administration of acrylamide to pregnant rats has been
shown to produce neurotoxic effects (tibial and optic nerve
degeneration) in neonates at levels that are non-toxic to the
dams (Dearfield et al., 1988). The lowest observed effect
occurred at doses of 20 mg/kg/day.
Edwards (1976) dosed pregnant rats with cumulative doses up
to 400 mg/kg between days 0 and 20 of gestation and found no
evidence of developmental or neurological abnormality in
weanling rats despite evidence of neuropathy in the dams.
No human data are available.
7.5 Mutagenicity
Acrylamide is regarded as a potential mutagen based on
experimental evidence that it can bind to DNA. The weight of
evidence however suggests that acrylamide does not produce
detectable gene mutations (Dearfield et al., 1988).
7.6 Interactions
Concurrent administration of methionine reduces the
neurotoxic potency of acrylamide (Hashimoto & Ando,
1971).
Supplementation of the diet with pyridoxine delays the onset
and severity of acrylamide toxicity in rats (Loeb & Anderson,
1981).
8. TOXICOLOGICAL ANALYSES & BIOMEDICAL INVESTIGATIONS
8.1 Material sampling plan
8.1.1 Sampling and specimen collection
8.1.1.1 Toxicological analyses
8.1.1.2 Biomedical analyses
8.1.1.3 Arterial blood gas analysis
8.1.1.4 Haematological analyses
8.1.1.5 Other (unspecified) analyses
8.1.2 Storage of laboratory samples and specimens
8.1.2.1 Toxicological analyses
8.1.2.2 Biomedical analyses
8.1.2.3 Arterial blood gas analysis
8.1.2.4 Haematological analyses
8.1.2.5 Other (unspecified) analyses
8.1.3 Transport of laboratory samples and specimens
8.1.3.1 Toxicological analyses
8.1.3.2 Biomedical analyses
8.1.3.3 Arterial blood gas analysis
8.1.3.4 Haematological analyses
8.1.3.5 Other (unspecified) analyses
8.2 Toxicological Analyses and Their Interpretation
8.2.1 Tests on toxic ingredient(s) of material
8.2.1.1 Simple qualitative test(s)
8.2.1.2 Advanced qualitative confirmation test(s)
8.2.1.3 Simple quantitative method(s)
8.2.1.4 Advanced quantitative method(s)
8.2.2 Tests for biological specimens
8.2.2.1 Simple qualitative test(s)
8.2.2.2 Advanced qualitative confirmation test(s)
8.2.2.3 Simple quantitative method(s)
8.2.2.4 Advanced quantitative method(s)
8.2.2.5 Other dedicated method(s)
8.2.3 Interpretation of toxicological analyses
8.3 Biomedical investigations and their interpretation
8.3.1 Biochemical analysis
8.3.1.1 Blood, plasma or serum
8.3.1.2 Urine
8.3.1.3 Other fluids
8.3.2 Arterial blood gas analyses
8.3.3 Haematological analyses
8.3.4 Interpretation of biomedical investigations
8.4 Other biomedical (diagnostic) investigations and their
interpretation
8.5 Overall interpretation of all toxicological analyses and
toxicological investigations
Following significant acute exposure, it is appropriate
to monitor serum electrolyte concentrations, blood glucose
concentration, hepatic and renal function, and blood
count.
There are no methods routinely available for determining
acrylamide or its metabolites in blood, urine or faeces.
Acute
Chest X-ray
Other investigations as dictated by clinical condition.
Chronic
* Nerve conduction studies.
Nerve conduction studies may reveal evidence of reduction in
maximal conduction velocity of peripheral nerves in severe
cases of peripheral neuropathy. More commonly, the maximal
conduction velocities recorded in acrylamide-poisoned
patients are within two standard deviations of control
values. The most consistent finding is a reduction in nerve
action potential amplitude in distal sensory nerves
(Fullerton, 1969). This test is likely to be more sensitive
if a pre-exposure baseline study is available for
comparison.
* Sural nerve biopsy
Characterstic histopathologic findings have been described in
sural nerve biopsy specimens from acrylamide-poisoned
individuals with clinical evidence of peripheral neuropathy
(Davenport et al., 1976). These findings include diffuse
fibrosis, loss of nerve fibres, enlarged axons,
neurofibrillary tangles, Wallerian degeneration and focal
dilation of myelin sheaths. On electron microscopy, axons
are seen to be packed with haphazardly-arranged fine
filaments.
Sural nerve biopsy is not recommended in the routine
evaluation of patients suspected of suffering from
acrylamide-induced peripheral neuropathy.
* Haemoglobin adducts
Measurement of haemoglobin adducts has been proposed as a
method of biomonitoring in acrylamide-exposed workers
(Calleman et al., 1994).
9. CLINICAL EFFECTS
9.1 Acute poisoning
9.1.1 Ingestion
There are only two reported cases of acute
acrylamide ingestion (Donovan & Pearson, 1987; Shelly,
1996; see section 11.1 for full details of these
cases). In both cases a symptom-free period of hours
was followed by progressive onset of severe
multi-system toxicity which included decreased level
of consciousness, seizures, hypotension and acute
adult respiratory distress syndrome. Delayed onset of
peripheral neuropathy was observed in both
cases.
9.1.2 Inhalation
No immediate clinical effects have been linked
to acute inhalational exposure.
9.1.3 Skin exposure
No immediate clinical effects have been linked
to acute dermal exposure.
9.1.4 Eye contact
No human data available.
Instillation of 10% aqueous solution into the
conjunctival sac of cats results in immediate minor
conjunctival irritation that resolves completely
within 24 hours. Instillation of 40% aqueous solution
results in minor conjunctival irritation and
significant corneal injury. Corneal injury is avoided
if the 40% solution is immediately rinsed following
instillation (McCollister et al., 1964)
9.1.5 Parenteral exposure
Not described in humans.
Parental administration of acrylamide to experimental
animals results in a state of generalised central
excitation including seizures following a latency
period that is inversely related to dose (Kuperman,
1958).
9.1.6 Other
Not relevant.
9.2 Chronic poisoning
9.2.1 Ingestion
Central and peripheral neurotoxicity is
described in a Japanese family when the well water
they used for drinking and cooking was contaminated
with 400 ppm of acrylamide. Members of the family
developed varying degrees of truncal ataxia and mental
confusion after an exposure of four weeks followed by
signs and symptoms of peripheral neuropathy somewhat
later as the central signs were improving. Complete
recovery occurred in all individuals over a period of
weeks to months following termination of the exposure
(Igusu et al., 1975).
9.2.2 Inhalation
Acrylamide is well absorbed following
inhalational exposure, and absorption via this route
is likely to be second only to skin absorption in
contributing to the development of neurotoxicity.
Neither immediate nor delayed local effects are
associated with inhalation.
Almost all reported cases of human acrylamide toxicity
have occurred in the context of chronic occupational
exposure with predominant routes believed to be
combined inhalational and dermal (see 11.1 for
detailed description of individual reported
cases).
The clinical course is characterized by the
development of symptoms and signs of a motor and
sensory peripheral neuropathy (see 9.4.3.2) that
slowly progress in severity if exposure continues.
Other prominent initial symptoms and signs are
excessive sweating of the hands and feet and
inflammation of the skin of the hands and feet with
blistering and desquamation. Muscle pain and weakness
are less common. If exposure is prolonged, evidence
of central nervous dysfunction develops, especially
truncal ataxia and behavioural change. Malaise and
weight loss are almost always reported.
There is considerable interindividual variation in the
severity, rapidity of progression and delay in onset
of symptoms following initial exposure. This is most
likely to reflect differences in the cumulative dose
of acrylamide that is absorbed.
9.2.3 Skin exposure
Acrylamide is well absorbed via the skin and
the majority of cases of poisoning have been ascribed
to repetitive dermal and inhalational exposure in
workers handling the monomer. The clinical syndrome
that develops in these workers is described above in
9.2.2.
9.2.4 Eye contact
Not relevant.
9.2.5 Parenteral exposure
Not relevant.
9.2.6 Other
Not relevant.
9.3 Course, prognosis, cause of death
Acute
Following acute ingestion, the patient remains symptom-free
for a period of hours depending on the dose ingested. The
initial sign of toxicity is usually behavioural change or
hallucinations. This may rapidly progress to a markedly
decreased level of consciousness and tonic-clonic seizures.
Hypotension and decreased cardiac output may develop soon
after the central nervous system manifestations. These
central nervous and cardiovascular manifestions may last many
days and be accompanied by toxicity of other systems
including the respiratory, gastroenterological and
haemotological systems. Peripheral neuropathy occurs as a
delayed effect and may not be evident until the patient is
recovering from the central nervous system and cardiovascular
effects. There are only two reported cases of severe
toxicity following acute ingestion and in both instances,
complete recovery occurred with aggressive supportive care.
The peripheral neuropathy may take from weeks to months to
completely resolve.
Chronic
The signs and symptoms of chronic occupational acrylamide
toxicity are progressive in nature for as long as exposure
above a certain critical dose continues.
Following removal from further exposure, the dermatitis
resolves relatively quickly and the peripheral neuropathy
resolves over a period of weeks to months. Central effects
such as truncal ataxia may take much longer to resolve and,
in severe cases, complete recovery may never occur (Murray &
Seger, 1994).
Death has not been reported from either acute or chronic
acrylamide exposure in humans.
9.4 Systematic description of clinical effects
9.4.1 Cardiovascular
Acute exposure
Hypotension requiring aggressive supportive care with
vasopressor agents occurred in both reported cases of
acute ingestion of acrylamide (Donovan & Pearson,
1987; Shelly, 1996).
Chronic exposure
Cardiovascular complications have not been described
in association with chronic exposure.
9.4.2 Respiratory
Acute exposure
Adult respiratory distress syndrome (ARDS) developed
some days following acute ingestion of acrylamide in
both reported cases (Donovan & Pearson, 1987; Shelly,
1996).
Chronic exposure
Respiratory complications have not been described in
association with chronic exposure.
9.4.3 Neurological
9.4.3.1 Central Nervous System (CNS)
Acute exposure
Hallucinations followed by seizures occurred
within a period of hours following acute
ingestion of acrylamide (Donovan & Pearson,
1987; Shelly, 1996).
Chronic exposure
Truncal ataxia is almost universally reported
in workers with moderate to severe acrylamide
toxicity. Other features suggesting CNS
toxicity include tremor and slurred speech.
The adult members of the Japanese family
poisoned by contaminated well water presented
with features of an acute organic brain
syndrome including vivid visual
hallucinations together with truncal ataxia
(Igisu et al., 1975). Mental confusion is
not a prominent feature in
occupationally-exposed individuals although
more subtle behavioural changes have been
noted.
9.4.3.2 Peripheral nervous system
Acute exposure
Delayed onset of peripheral neuropathy is
reported following acute ingestion of
acrylamide. Complete recovery occurred in
both cases (Donovan & Pearson, 1987; Shelly,
1996).
Chronic exposure
Peripheral neuropathy is the cardinal
manifestation of occupational acrylamide
toxicity and its symptoms are the most
frequent presentation of this condition. The
peripheral neuropathy has both motor and
sensory components and progresses in severity
if exposure continues. Symptoms initially
involve the hands and feet and may progress
to involve the entire upper and lower
extremities. Symptoms include paraesthesiae
and numbness, coldness, and difficulty with
fine movements such as writing. Signs
include impaired touch or vibration sense in
a glove and stocking distribution, impaired
joint position sense, absent tendon reflexes
and atrophy of the small muscles of the hand.
Complete recovery usually occurs over a
period of weeks to months following removal
of the worker from further
exposure.
9.4.3.3 Autonomic nervous system
Excessive sweating of the
extremities is an early and almost universal
symptom of chronic acrylamide toxicity. It
has not been reported following acute
ingestion.
9.4.3.4 Skeletal and smooth muscle
Muscle pain is sometimes reported as
an early symptom of occupational exposure.
Frank loss of power may occur in advanced
cases of toxicity. Muscle wasting has been
reported only in the intrinsic muscles of the
hand.
9.4.4 Gastrointestinal
Acute
Gastrointestinal bleeding occurred following acute
ingestion of acrylamide (Donovan & Pearson, 1987). A
moderate elevation in serum amylase is reported
following acute exposure (Shelly, 1996).
Chronic
Weight loss despite a normal appetite is frequently
reported in association with chronic occupational
exposure to acrylamide.
9.4.5 Hepatic
Acute
Hepatoxicity is reported following acute ingestion of
acrylamide (Donovan & Pearson, 1987; Shelly,
1996).
Chronic
Hepatoxicity has not been reported in association with
subacute or chronic exposure.
9.4.6 Urinary
9.4.6.1 Renal
Transient impairment in renal
function has been reported following acute
ingestion (Shelly, 1996). It was considered
a complication of decreased cardiac
output.
9.4.6.2 Others
Urinary retention and incontinence
have been reported in association with
occupational exposure.
9.4.7 Endocrine & reproductive systems
Not reported.
9.4.8 Dermatological
Acute
Dermatological manifestations of toxicity have not
been reported following acute exposure.
Chronic
Local dermatitis, usually involving the hands, with
mild erythema and peeling of the skin is an early
effect of exposure and usually precedes the
development of peripheral neuropathy.
Eczema, with a patch-test positive for acrylamide,
developed in a worker handling acrylamide despite the
use of polyvinylchloride gloves (Dooms-Gossens et al.,
1991).
9.4.9 Eye, ears, nose, throat: local effects
Two adults exposed to contaminated well water
reported rhinorrhoea as their initial symptom (Igusu
et al., 1975). This has not been reported in cases of
occupational exposure.
9.4.10 Haematological
Acute
Thrombocytopenia has been reported following acute
exposure (Shelly, 1996).
Chronic
Haematological complications have not been
reported.
9.4.11 Immunological
Not reported.
9.4.12 Metabolic
9.4.12.1 Acid-base disturbances
Severe metabolic acidosis occured
within hours of acute ingestion of acrylamide
(Shelley, 1996).
9.4.12.2 Fluid & electrolyte disturbances
No data available.
9.4.12.3 Others
No data available.
9.4.13 Allergic reactions
Eczema has been reported (See 9.4.8).
9.4.14 Other clinical effects
Fatigue and somnolence are frequently reported
in association with occupational exposure.
9.4.15 Special risks
No data available on risks associated with
pregnancy or lactation.
9.5 Others
Acute
Toxicity following acute ingestion of acrylamide is
characterized by an initial symptomatic period lasting
several hours followed by progressive onset of a central
nervous system disturbance, including seizures, and then
subsequent multisystem dysfunction. Delayed peripheral
neuropathy occurs as the other features of toxicity are
resolving. Eventual complete recovery is possible if
aggressive supportive care is instituted.
Chronic
Chronic acrylamide toxicity is characterized by local
dermatitis, excessive sweating, fatigue, weight loss and
features of progressive CNS disturbance (especially truncal
ataxia) and peripheral neuropathy. The severity of symptoms
and the rapidity of onset appears to relate to the duration
of exposure to, and the daily dose of, acrylamide. Recovery
over a period of weeks to months following removal from
exposure is the usual course.
9.6 Summary
10. MANAGEMENT
10.1 General principles
Acute
Patients with a history of acute acrylamide ingestion should
be admitted for 24 hours of careful observation of
cardiorespiratory function and neurological status. Gastric
decontamination may be appropriate following early
presentation. The management of established toxicity is
careful supportive care including maintenance of airway,
breathing and circulation and control of seizures.
Chronic
There is no specific therapy for acrylamide dermatitis,
encephalopathy or peripheral neuropathy other than removal
from further exposure. Prevention of exposure by rigorous
enforcement of safety standards in the workplace and worker
education is most important (see section 12.2). Exposed
workers who develop neurological symptoms should be removed
from any employment where further acrylamide exposure may
occur.
10.2 Life supportive procedures
Emergency institution of measures designed to maintain
airway, breathing and circulation may be necessary in the
rare event of a massive acute exposure to acrylamide. Such
measures might include endotracheal intubation, assisted
ventilation, administration of supplemental oxygen,
pharmacologic control of seizures and administration of
intravenous fluids and vasopressors. Even following a
massive acute exposure, there is likely to be a significant
delay (usually several hours) prior to the onset of seizures
and/or cardiorespiratory failure.
10.3 Decontamination
Because acrylamide is well absorbed via the skin, the
skin should be thoroughly washed following acute dermal
exposure. Exposed workers should wash after each shift and
their clothing should be removed and washed after each
shift.
Following inhalational exposure, the victim should be removed
to fresh air as soon as possible.
Following acute eye exposure, the eyes should be thoroughly
rinsed with water for several minutes.
Following acute ingestion, induction of emesis is not
indicated because of the risk of subsequent seizures. Gastric
emptying by lavage may be of value if performed as soon as
practicable in the awake patient or following endotracheal
intubation in the obtunded patient. It is not known whether
activated charcoal effectively binds acrylamide but its
administration soon after a significant acute ingestion is
reasonable. The oral cavity should be rinsed after ingestion
of acrylamide.
10.4 Elimination
There are no effective methods available to enhance the
elimination of absorbed acrylamide.
10.6 Antidote treatment
10.6.1 Adults
There is no antidote available for which
efficacy has been established (see 10.6 for further
discussion).
10.6.2 Children
There is no antidote available for which
efficacy has been established (see 10.7 for further
discussion).
10.6 Management discussion
Acute
It has been suggested that pyridoxine may reduce
neurotoxicity if administered soon after a massive acute
exposure (Loeb & Anderson, 1981).
This suggestion is based on observations in laboratory
animals and the efficacy of pyridoxine in human poisoning is
unsubstantiated. Although an appropriate dose of pyridoxine
in this circumstance is unknown, an intravenous dose of 5 g
of 10% solution over 30 minutes is reasonable (such high
doses are administered without toxic complication to patients
following isoniazid overdose).
Because acrylamide undergoes biotransformation by conjugation
with glutathione, the administration of N-acetyl cysteine or
other agents that replenish hepatic glutathione stores is of
theoretical benefit immediately following massive acute
exposure. The therapeutic benefit of this therapy has not
been evaluated although methionine reduced the neurotoxicity
of acrylamide in rats (see section 7.6).
Chronic
At present there is no adequate monitoring test available for
use in exposed workers. Arezzo et al. (1983) have proposed
the use of a quantitative measure of the threshold of
vibration sensation in the fingers and toes. Calleman et al.
(1994) have proposed biomonitoring of acrylamide-exposed
workers by the measurement of haemoglobin adducts. The
usefulness of these tests requires further evaluation.
In established cases of acrylamide toxicity, the only
treatment is removal from further exposure. This should take
place at least until complete resolution of all symptoms and
signs of toxicity occurs. This may take from weeks to months
or, in severe cases, may never occur. It is controversial as
to whether poisoned workers should return to handling
acrylamide even if complete recovery is documented. There is
some evidence from animal experiments that such individuals
may be more sensitive to toxicity upon reexposure.
In terms of environmental contamination, the chief danger to
humans appears to be from ground water contamination.
Particular care must be taken to prevent ground water
contamination during grouting operations. Where such
contamination occurs it is essential to prevent consumption
by humans of the contaminated water.
11. ILLUSTRATIVE CASES
11.1 Case reports from literature
Auld & Bedwell (1967) reported a 21-year-old male
admitted to hospital with a seven-week history of progressive
rash, fatigue, weakness of the upper and lower extremities
and profuse sweating of the extremities. He had spent 35
hours/week for each of the preceding 14 weeks working in a
mine, loading a 10% aqueous solution of acrylamide into a
hopper, adding a catalyst (B-dimethyl-amino-propionitrile)
and then pumping the mixture into the soil. Extensive dermal
contact with acrylamide was reported. Physical examination
was notable for bluish-red discoloration and profuse sweating
of all extremities and evidence of a peripheral neuropathy
(decreased temperature sensation, light touch, joint position
sense and vibration and absent tendon reflexes of the lower
limb). Gradual and complete resolution of symptoms and signs
occurred over the next 14 weeks following removal from
further exposure to acrylamide.
Garland & Patterson (1967) reported a series of six workers
from 3 factories making flocculators from acrylamide. All
workers had extensive dermal contact with acrylamide. All
six developed ataxia and clinical evidence of peripheral
neuropathy following an exposure ranging from 4 to 60 weeks.
Other prominent symptoms included profuse sweating of the
extremities, erythema and peeling of the skin of the hands,
and fatigue. The less severely affected cases made complete
recovery over a period of weeks. The two most severely
affected cases remained symptomatic some months later.
Igusu et al. (1975) reported a family of five who developed
central nervous system disturbances including hallucinations,
mental confusion, behavioural disturbance and severe truncal
ataxia over a period of one month following contamination of
their well water with acrylamide from road grouting carried
out within 2.5 meters of the well. Acrylamide concentrations
in the well water were measured at 400 ppm and the family
used the water for drinking, cooking and bathing. The
central nervous symptoms resolved within two weeks of
cessation of exposure at about which time the development of
a sensory peripheral neuropathy was noted in the three more
severely affected cases. Complete recovery occurred in all
cases by four months.
Davenport et al. (1976) reported a 25-year-old admitted to
hospital with loss of sensation and unsteady gait after
working with acrylamide for six months. His job involved
mixing acrylamide powder with other reagents in a sealed
reactor vessel. The initial reported symptom was irritation
and erythema of the palms and soles beginning several weeks
after exposure began, followed by several months of fatigue,
anorexia and weight loss with ataxia developing two weeks
before presentation. Examination revealed excessive sweating
and blistering of the hands and feet, evidence of a
peripheral sensory neuropathy, mild weaknes of the muscles of
the ankles and wrists and an ataxic gait. Electrophysiologic
studies confirmed a peripheral neuropathy with prolonged
distal motor latencies and poor or absent sensory conduction.
Sural nerve biopsy revealed diffuse fibrosis and loss of
nerve fibres, focal dilation of the myelin sheath and, on
electron-microscopy, axons packed with bundles of fine
filaments. There was no progression or regression of
clinical findings over the ensuing two months without
reexposure to acrylamide.
Kesson et al. (1977) reported a 57-year-old male whose
employment involved the polymerization of acrylamide monomer
in the confines of a small concrete tunnel. He complained of
increased sweating, peeling of the skin of the hands and
tingling and weakness of the hands. Examination revealed
evidence of peripheral neuropathy. Evaluation of the
worksite identified five other less severely affected workers
and all reported onset of skin irritation within two weeks of
starting to handle acrylamide. The index case and one other
showed little clinical improvement at one year after
cessation of further exposure to acrylamide.
Donovan & Pearson (1987) described the only reported case of
toxicity following single oral ingestion of acrylamide. A
23-year-old female intentionally ingested 18 g of acrylamide
crystal as a suicide gesture. Asymptomatic on presentation,
she developed hallucinations and hypotension five hours later
followed by seizures at nine hours post-ingestion. The
subsequent clinical course was stormy and characterized by
gastointestinal bleeding, adult respiratory distress
syndrome, hepatotoxicity and peripheral neuropathy beginning
on day 3. She survived with intensive supportive care to be
discharged at three weeks post-ingestion but still had
evidence of peripheral neuropathy at follow-up two months
later.
Murray & Seger (1994) reported a mineworker with evidence of
acrylamide neurotoxicity who remained disabled ten years
after cessation of prolonged inhalational exposure to
acrylamide monomer.
12. ADDITIONAL INFORMATION
12.1 Specific preventive measures
Management centres on prevention of toxicity in workers
at risk. Fundamental to this process are education and
hygiene. Workers need to be aware that acrylamide is a
potent neurotoxin and that is is easily absorbed via the
skin, respiratory tract or gastrointestinal tract. The need
to be aware that the effects of exposure, although not
immediately noticeable, are cumulative. Workers should be
familiar with the initial symptoms of acrylamide exposure,
especially skin peeling, excessive fatigue, abnormal
sweating, problems with balance, and "pins and needles" or
loss of feeling in the feet or hands. They should be
encouraged to report any such symptoms.
Dermal and inhalational contact with acrylamide monomer
should be rigourously avoided. Ideally this involves the
development of closed systems for handling acrylamide
monomer. If at all possible, handling of the monomer in a
confined space should be avoided. Workers handling the agent
should wear long polyvinyl gloves, washable overalls and head
covers and facemasks that will prevent inhalation of dust.
Eating at the workplace should be prohibited. Workers should
wash thoroughly at the end of each shift and after any
unintentional exposure. Work clothing should be washed
daily.
Clear warnings of the danger of exposure should be on all
packaging for acrylamide.
12.2 Other
Not relevant.
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14. AUTHOR(S), REVIEWER(S), ADDRESS(ES), DATE(S) (INCLUDING UPDATES)
Author: Lindsay Murray
Center for Clinical Toxicology
501 Oxford House
Vanderbilt University Medical Center
Nashville, TN 37232
USA
Tel: +1-615-9360760
Fax: +1-615-9360756
Date: July 1996
Reviewer: Wayne Temple
National Toxicology Group
University of Otago
Dunedin
New Zealand
Date: August 1996
Peer
review: Cardiff, United Kingdom, September 1996
(Review group members: A. Borges, A. Brown, R. Ferner,
M. Hanafy, L. Murrray, M.O. Rambourg, W. Temple)
Editor: Mrs J. Dum駭il
International Programme on Chemical Safety
Date: June 1999