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

    World Health Orgnization
    Geneva, 1985

         The International Programme on Chemical Safety (IPCS) is a
    joint venture of the United Nations Environment Programme, the
    International Labour Organisation, and the World Health
    Organization. The main objective of the IPCS is to carry out and
    disseminate evaluations of the effects of chemicals on human health
    and the quality of the environment. Supporting activities include
    the development of epidemiological, experimental laboratory, and
    risk-assessment methods that could produce internationally
    comparable results, and the development of manpower in the field of
    toxicology. Other activities carried out by the IPCS include the
    development of know-how for coping with chemical accidents,
    coordination of laboratory testing and epidemiological studies, and
    promotion of research on the mechanisms of the biological action of

        ISBN 92 4 154189 X    

         The World Health Organization welcomes requests for permission
    to reproduce or translate its publications, in part or in full.
    Applications and enquiries should be addressed to the Office of
    Publications, World Health Organization, Geneva, Switzerland, which
    will be glad to provide the latest information on any changes made
    to the text, plans for new editions, and reprints and translations
    already available.

    (c) World Health Organization 1985

         Publications of the World Health Organization enjoy copyright
    protection in accordance with the provisions of Protocol 2 of the
    Universal Copyright Convention. All rights reserved.

         The designations employed and the presentation of the material
    in this publication do not imply the expression of any opinion
    whatsoever on the part of the Secretariat of the World Health
    Organization concerning the legal status of any country, territory,
    city or area or of its authorities, or concerning the delimitation
    of its frontiers or boundaries.

         The mention of specific companies or of certain manufacturers'
    products does not imply that they are endorsed or recommended by the
    World Health Organization in preference to others of a similar
    nature that are not mentioned. Errors and omissions excepted, the
    names of proprietary products are distinguished by initial capital




    1.1. Summary
         1.1.1. Properties, uses, and analytical methods
         1.1.2. Environmental sources and environmental
                transport and distribution
         1.1.3. Environmental levels and exposures
         1.1.4. Metabolism of acrylamide
         1.1.5. Effects on man and animals
         1.1.6. Mutagenicity and carcinogenicity
         1.1.7. Teratogenicity and reproduction
         1.1.8. Dose-effect and dose-response relationships
         1.1.9. Evaluation of health risks for man
    1.2. Recommendations for further research
         1.2.1. Analysis
         1.2.2. Exposure
         1.2.3. Metabolism and indicators of exposure
         1.2.4. Effects


    2.1. Identity
    2.2. Chemical and physical properties
    2.3. Sampling and analytical methods


    3.1. Production levels, processes, and uses
         3.1.1. World production
         3.1.2. Production processes
         3.1.3. Uses
    3.2. Release into the environment
    3.3. Disposal of wastes


    4.1. Transport in the environment
    4.2. Biomagnification and bioconcentration
    4.3. Transformation


    5.1. Environmental levels
         5.1.1. Ambient air and soil
         5.1.2. Water
         5.1.3. Food
    5.2. General population exposure
    5.3. Occupational exposure


    6.1. Experimental animal studies
         6.1.1. Absorption and distribution
         6.1.2. Metabolism
         6.1.3. Elimination and excretion
    6.2. Human studies


    7.1. Neurological effects
         7.1.1. Neurobehavioural effects
         7.1.2. Electrophysiological effects
        Peripheral effects
        Central nervous system effects
         7.1.3. Morphological effects
         7.1.4. Biochemical effects
        Effects on axonal transport
        Effects on energy production
                         and neuronal metabolism
        Effects on CNS neurochemistry
    7.2.  In vitro toxicity studies
    7.3. Effects on other organs
    7.4. Genotoxic effects and carcinogenicity studies
         7.4.1. Mutagenicity and other related short-term tests
         7.4.2. Carcinogenicity studies
    7.5. Teratogenicity and reproductive studies
    7.6. Factors modifying effects
         7.6.1. Chemical modification of acrylamide toxicity
         7.6.2. Age
         7.6.3. Sex differences
         7.6.4. Species
    7.7. Dose-response and dose-effect relationships
         7.7.1. Dose-response relationships
         7.7.2. Dose-effect relationships
        Manifestations of neuropathy
        Electrophysiological effects
        Morphological effects
        Effects on axonal transport
        Neurobehavioural effects


    8.1. Clinical studies and case reports
    8.2. Epidemiological studies
    8.3. Dose-effect and dose-response relationships


    9.1. Aquatic organisms
         9.1.1. Invertebrates
         9.1.2. Fish and amphibia
    9.2. Terrestrial plants
    9.3. Microorganisms



    11.1. General considerations
    11.2. Assessment of exposure
    11.3. Assessment of adverse effects
    11.4. Exposure of the environment
    11.5. Occupational exposure




Dr N. Aldridge, Medical Research Council, Carshalton, Surrey,
   United Kingdom  (Chairman)

Dr M. Berlin, Monitoring and Assessment Research Centre,
   University of London, London, United Kingdom

Prof J. Cavanagh, Institute of Neurology, London, United

Dr K. Hashimoto, Department of Hygiene, School of Medicine,
   Kanazawa University, Ishikawa, Japan  (Vice-Chairman)

Dr D.G. Hatton, US Food and Drug Administration, Department of
   Health and Human Services  (Rapporteur)

Prof M. Ikeda, Department of Environmental Health, Tohoku
   University School of Medicine, Sendai, Japan

Dr P. Le Quesne, National Hospital for Nervous Diseases,
   London, United Kingdom

Prof A. Massoud, Ain Shams University, Cairo, Egypt

Dr P.K. Ray, Industrial Toxicology Research Centre, Lucknow,

Prof I.V. Sanotsky, Research Institute of Industrial Hygiene
   and Occupational Diseases, USSR Academy of Medical
   Sciences, Moscow, USSR

Dr H.A. Tilson, Laboratory of Behavioral and Neurological
   Toxicology, NIEHS, Research Triangle Park, North Carolina,

 Representatives from Other Organizations

Mr S. Batt, Monitoring and Assessment Research Centre,
   University of London, London, United Kingdom

Dr L. Shukar, Monitoring and Assessment Research Centre,
   University of London, London, United Kingdom

Mr J.D. Wilbourn, International Agency for Research on Cancer,
   Unit of Carcinogen Identification and Evaluation, Lyons,

 WHO Secretariat

Dr M. Draper, International Programme on Chemical Safety,
   World Health Organization, Geneva, Switzerland

Dr E.M.B. Smith, International Programme on Chemical Safety,
   World Health Organization, Geneva, Switzerland  (Secretary)

Ms A. Sunden, International Register of Potentiallly Toxic
   Chemicals, Geneva, Switzerland


    While every effort has been made to present information in 
the criteria documents as accurately as possible without unduly 
delaying their publication, mistakes might have occurred and are 
likely to occur in the future.  In the interest of all users of 
the environmental health criteria documents, readers are kindly 
requested to communicate any errors found to the Manager of the 
International Programme on Chemical Safety, World Health 
Organization, Geneva, Switzerland, in order that they may be 
included in corrigenda, which will appear in subsequent volumes. 

    In addition, experts in any particular field dealt with in 
the criteria documents are kindly requested to make available to 
the WHO Secretariat any important published information that may 
have inadvertently been omitted and which may change the 
evaluation of health risks from exposure to the environmental 
agent under examination, so that the information may be 
considered in the event of updating and re-evaluation of the 
conclusions contained in the criteria documents. 

                           *   *   *

     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. 988400 -


    Following the recommendations of the United Nations 
Conference on the Human Environment held in Stockholm in 1972, 
and in response to a number of World Health Assembly resolutions 
(WHA23.60, WHA24.47, WHA25.58, WHA26.68), and the recommendation 
of the Governing Council of the United Nations Environment 
Programme, (UNEP/GC/10, 3 July 1973), a programme on the 
integrated assessment of the health effects of environmental 
pollution was initiated in 1973.  The programme, known as the WHO 
Environmental Health Criteria Programme, has been implemented 
with the support of the Environment Fund of the United Nations 
Environment Programme.  In 1980, the Environmental Health 
Criteria Programme was incorporated into the International 
Programme on Chemical Safety (IPCS).  The result of the 
Environmental Health Criteria Programme is a series of criteria 

    A WHO Task Group on Environmental Health Criteria for 
Acrylamide was held at the British Industries Biological Research 
Association (BIBRA), Carshalton, Surrey, United Kingdom, from 
3-5 December, 1984.  Dr E.M.B. Smith opened the meeting on behalf 
of the Director-General.  The Task Group reviewed and revised the 
draft criteria document and made an evaluation of the health risks 
of exposure to acrylamide. 

    The initial draft was prepared by DR M. BERLIN with the 
assistance of DR L. SHUKAR and MR S. BATT of the MONITORING AND 

    The efforts of all who helped in the preparation and 
finalization of the document are gratefully acknowledged. 

                           * * *

    Partial financial support for the publication of this 
criteria document was kindly provided by the United States 
Department of Health and Human Services, through a contract from 
the National Institute of Environmental Health Sciences, Research 
Triangle Park, North Carolina, USA - a WHO Collaborating Centre 
for Environmental Health Effects.  The UK Department of Health 
and Social Security generously supported the cost of printing. 


1.1.  Summary

1.1.1.  Properties, uses, and analytical methods

    Acrylamide is a white crystalline solid produced from 
acrylonitrile, which is present as a residue in technical grades 
of acrylamide at concentrations ranging from 1 to 100 mg/kg.  
Acrylamide readily undergoes polymerization, resulting in a 
highly cross-linked insoluble gel of polyacrylamide.  Commercial 
polyacrylamide contains 0.05 - 5.0% acrylamide.  Hydroquinone 
monomethylether, t-butylpyrocatechol,  N-phenyl-2-naphthylamine, 
and copper (ion) may be used as stabilizers. 

    Acrylamide is mainly used in the production of polymers and 
copolymers for various purposes.  Polyacrylamides are useful as 
flocculents in the treatment of waste water and the purification 
of drinking-water.  Acrylamide is also used as a grouting agent 
and in the construction of dam foundations and tunnels. 

    Methods for the determination of acrylamide in polymers, air, 
water, and biological materials have been devised using gas 
chromatography, high-performance liquid chromatography, and 
differential pulse polarography.  No method has so far been 
described for the determination of either acrylamide bound to 
blood and tissue proteins or its metabolites in the urine. 

    The reported sensitivity for the determination of acrylamide 
in air, using gas chromatography, is 5 g/m3 and, using electron 
capture and flame ionization detection, 30 g/m3.  Sampling of 
acrylamide (vapour and dust) in air is performed using midget 
impingers.  Determination of acrylamide in polyacrylamide can be 
accomplished, with a sensitivity of less than 1 mg/kg, using 
differential pulse polarography.  The detection limit for 
acrylamide in water is 0.1 g/litre, using electron capture gas 
chromatography after derivatization, though the recovery of 
acrylamide is rather poor.  Derivatization followed by high-
performance liquid chromatography is less sensitive (0.2 g/litre), 
but is more suitable for the routine analysis of both natural and 
polluted water.  Free acrylamide in biological samples such as 
plasma and tissue homogenates can be determined, by electron 
capture-gas chromatography, with a detection limit of 10 

1.1.2.  Environmental sources and environmental transport and 

    All acrylamide in the environment is man-made, the main 
source being the release of the monomer residues from 
polyacrylamide used in water treatment or in industry.  The most 
important environmental contamination results from the use of 
acrylamide in soil grouting, because of contamination of ground 
water.  Chemical decontamination of acrylamide-containing liquid 
wastes and solids is possible, but the costs, in most instances, 
are high. 

    Because it is highly soluble in water, acrylamide is 
extremely mobile in the aqueous environment and is readily 
leachable in soil.  It is unlikely to enter and be transported in 
the atmosphere to any significant extent, because of its low 
vapour pressure.  Biodegradation is likely to occur. 

    A wide variety of microbes possess the ability to degrade 
acrylamide.  However, there is a latent period of several days 
before there is any significant degradation.  The residence 
period for acrylamide may be of the order of days, weeks, or 
months, in rivers and coastal areas of low microbial activity.  
The half-life in aerobic soil, which is of the order of several 
days at 20 C, increases with decreasing temperature. 

    Acrylamide is unlikely to be removed during sewage treatment 
and has been shown to pass through waterworks mainly unchanged. 

1.1.3.  Environmental levels and exposures

    Because polyacrylamide is used in water treatment, residues 
of acrylamide may be found in potable water.  In most countries, 
such residues are limited to 0.25 g/litre by maintaining the 
concentration of acrylamide monomer in the polyacrylamide used 
for water treatment at 0.05%.  Concentrations of acrylamide in 
effluents from polyacrylamide-using factories generally range 
from less than 1 to 50 g/litre.  However, 1.5 mg 
acrylamide/litre has been measured downstream from industrial 
effluent discharges.  Levels reported in receiving streams and 
rivers are variable and dependent on the extent of dilution.  A 
level of 0.3 g/litre was detected at a waterworks intake 
downstream from an effluent discharge from a clay pit.  In the 
vicinity of local grouting operations, high levels of acrylamide 
may be found in wells and ground water; a concentration of 400 
mg/litre was reported in one such well. 

    Monitoring of acrylamide concentrations in air and soil close 
to 6 acrylamide-producing plants in the USA failed to demonstrate 
any acrylamide in the air (detection limit 0.1 g/m3) or in the 
soil (detection limit 0.02 mg/kg). 

    Polyacrylamides are also used in the washing and packaging of 
prepacked foods and vegetables.  The US Food and Drug 
Administration has limited the amount of monomer in 
polyacrylamide for use in paper or cardboard in contact with food 
to 0.2% (2 g/kg).  In the Federal Republic of Germany, the level 
of polyacrylamide used in foodstuff packaging is limited to 0.3% 
(3 g/kg) and the level of residual acrylamide monomer to 0.2% 
(2 g/kg)a. 

a   Bundesministerium fr Jugend, Familie und Gesundheit,
    personal communication, 1984.

    Occupational exposure to acrylamide occurs mainly through 
skin absorption and inhalation in acrylamide-producing plants.  
Personal sampling in such plants has shown average levels in 
workplace air of about 0.6 mg/m3, with a range of 0.1 - 3.6 mg/m3 
in heavily-exposed areas.  Measurements resulting from stationary 
sampling were generally 2 - 3 times lower.  This indicates the 
importance of taking work procedures into account in the 
assessment of exposure.  Published figures from the USA indicate 
that about 20 000 workers may be exposed to acrylamide.  Although 
exposure levels have not been reported for grouters, the 
potential for hazard from this use is probably greater than from 
other uses, because of the uncontrolled nature of the exposure. 

1.1.4.  Metabolism of acrylamide

    Acrylamide is readily absorbed by ingestion, inhalation, and 
through the skin.  Absorbed acrylamide is distributed in body 
water compartments and passes through the placental barrier.  In 
rats, biotransformation of acrylamide occurs through glutathione 
conjugation and through decarboxylation.  At least 4 urinary 
metabolites have been found in rat urine, of which mercapturic 
acid and cysteine- S-propionamide have been identified.  
Acrylamide and its metabolites are accumulated (protein-bound) in 
both nervous system tissue and blood (bound to haemoglobin).  
Accumulation in the liver and kidney as well as the male 
reproductive system has also been demonstrated.  The results of 
animal studies indicate that acrylamide is largely excreted as 
metabolites in urine and bile.  Because of the enterohepatic 
circulation of biliary metabolites, faecal excretion is minimal.  
Two-thirds of the absorbed dose is excreted with a half-life of a 
few hours.  However, protein-bound acrylamide or acrylamide 
metabolites in the blood, and possibly in the central nervous 
system, have a half-life of about 10 days.  The net elimination 
in urine of acrylamide metabolites is constant in the rat and is 
independent of dose within the range 1 - 200 mg/kg body weight.  
Acrylamide has been identified in rat milk during lactation.  
There are no data indicating any major differences in acrylamide 
metabolism between man and other mammals. 

1.1.5.  Effects on man and animals

    Acrylamide is toxic and an irritant.  Cases of acrylamide 
poisoning show signs and symptoms of local effects due to 
irritation of the skin and mucous membranes and systemic effects 
due to the involvement of the central, peripheral, and autonomic 
nervous systems.  Local irritation of the skin or mucous 
membranes is characterized by blistering and desquamation of the 
skin of the hands (palms) and feet (soles) combined with blueness 
of the hands and feet.  Effects on the central nervous system are 
characterized by abnormal fatigue, sleepiness, memory 
difficulties, and dizziness.  With severe poisoning, confusion, 
disorientation, and hallucinations occur.  Truncal ataxia is a 
characteristic feature, sometimes combined with nystagmus and 
slurred speech.  Excessive sweating in the limb extremities is a 
common observation. 

    Signs of central nervous system and local skin involvement 
may precede peripheral neuropathy by as much as several weeks.  
Peripheral neuropathy can involve loss of tendon reflexes, 
impairment of vibration sense, loss of other sensation, and 
muscular wasting in peripheral parts of the extremities.  Nerve 
biopsy shows loss of large diameter nerve fibres as well as 
regenerating fibres.  Autonomic nervous system involvement is 
indicated by excessive sweating, peripheral vasodilation, and 
difficulties in micturition and defaecation.  After cessation of 
exposure to acrylamide, most cases recover, although the course 
of improvement is prolonged and can extend over months to years. 

    In animal studies, early changes in visual-evoked potentials 
(VEP), preceding clinical signs, as well as changes in 
somatosensory-evoked potentials (SEP), have been seen. 
Morphological studies have revealed degenerative changes 
principally in peripheral nerve axons, with less severe changes 
in the longer fibres of the central nervous system.  Degeneration 
of Purkinje cells has been observed in chronically-intoxicated 
animals.  The changes are most pronounced in the nerve endings of 
myelinated sensory fibres.  The nerve endings show enlarged 
"boutons terminaux" and a widespread enlargement of nerve terminals 
from the accumulation of neurofilaments.  This occurs in both the 
peripheral and central nervous systems.  Impairment of retrograde 
and, to a lesser degree, anterograde axonal transport has been 
found in sensory fibres, and interference with glycolysis and 
protein synthesis, the latter preceding the onset of clinical 
signs, has been observed in biochemical studies.  Studies of 
neurotransmitter distribution and receptor binding in the brains of 
rats have revealed changes induced by acrylamide.  In rats, changes 
in the concentration of neurotransmitters and in striatal dopamine 
receptor binding have been related to behavioural changes. 

    Degenerative changes in renal convoluted tubular epithelium 
and glomeruli and fatty degeneration and necrosis of the liver 
have been seen in monkeys given large doses of acrylamide.  In 
rats, impairment of hepatic porphyrin metabolism has been 

1.1.6.  Mutagenicity and carcinogenicity

    Acrylamide (> 99% pure) was not mutagenic in  Salmonella 
 typhimurium in the presence or absence of a metabolic activation 

    Acrylamide of unknown purity induced chromosomal aberrations 
in the spermatocytes of male mice and was reported to increase 
cell transformation frequency in Balb 3T3 cells, in the presence 
of a metabolic activation system. 

    Acrylamide was shown to be an initiator for skin tumours in 
mice when administered by various routes.  It increased the 
incidence of lung tumours in mice-screening assays. 

    A 2-year study on rats administered acrylamide in the 
drinking-water has been conducted but has not been fully reported 
or evaluated. 

    No epidemiological data on cancer due to exposure to 
acrylamide are available and, from the available data, it is not 
possible to form a conclusion concerning the carcinogenicity of 

1.1.7.  Teratogenicity and reproduction

    There is no evidence in either man or animals of any gross 
teratogenic effects resulting from acrylamide exposure. 
Absorption of acrylamide by the fetus has been demonstrated in 
animal (pig, dog, rabbit, rat) studies.  Oral administration of 
acrylamide, between the 7 - 16th days of gestation in rats, 
decreased the binding of dopamine receptors in the striatal 
membranes in 2-week-old pups, a fact that may be explained by 
postnatal exposure through lactation as well as prenatal effects.  
Degeneration of seminiferous tubules, and chromosome aberrations 
in spermatocytes have been seen in acrylamide-treated male mice.  
Depressed plasma levels of testosterone and prolactin have also 
been observed.  However, fertility studies have not been 

1.1.8.  Dose-effect and dose-response relationships

    A total of over 60 cases of acrylamide poisoning in man have 
been reported in the literature.  No human epidemiological 
studies relating exposures to effects are available; the current 
lack of methods for biological monitoring or assessing the extent 
of exposure makes such studies impossible.  From clinical 
experience, it appears that acute exposure to high doses of 
acrylamide induces signs and symptoms of effects on the central 
nervous system, whereas peripheral neuropathy is a feature of 
long-term cumulative exposure to smaller doses.  Peripheral signs 
of neuropathy appear after a latent period.  This latent period 
is dose-dependent and decreases with increasing dose.  In animal 
studies, the onset of peripheral neuropathy parallels the 
accumulation of acrylamide bound to protein in the nervous system 
and, similarly, acrylamide bound to haemoglobin in erythrocytes. 

    The LD50 was of the same order of magnitude for all mammals 

    A statistically-significant increase in the incidence of 
mesothelioma of the scrotal cavity was observed in rats after 
long-term (2-year) administration in the drinking-water of 
acrylamide at 0.5 mg/kg body weight per day.  There are no 
reports of increases in any other types of tumour at this dose 
level.  However, administration over 2 years of 2 mg 
acrylamide/kg body weight per day not only increased the 
incidence of a variety of tumour types (both benign and 
malignant) but also decreased the life expectancy in both male 
and female rats.  The smallest long-term dose of acrylamide 

reported in one study to be associated with adverse neurological 
effects in rats was 1 mg/kg body weight per day.  This dose caused 
morphological changes in the sciatic nerves. 

1.1.9.  Evaluation of health risks for man

    There are insufficient epidemiological data regarding 
occupational or environmental exposure to acrylamide to serve as 
a basis for a quantitative risk evaluation.  Experimental animal 
data indicate that there are no major species differences among 
mammals with respect to acrylamide metabolism or sensitivity to 
its neurotoxic effects.  Extrapolation from animal dose-effect 
data suggests that an absorbed dose of 0.12 mg/kg body weight per 
day (derived from total dose to surface area data) could cause 
adverse neurological effects in man.  As acrylamide is readily 
absorbed through the skin and by inhalation and ingestion, these 
effects are probably independent of the route of exposure.  
Applying a safety factor of 10 to the extrapolated minimum dose 
for neurological effects would indicate that an absorbed dose of 
0.012 mg/kg body weight per day should not be exceeded.  Animal 
data are not sufficient to draw any conclusions concerning the 
carcinogenicity of acrylamide.  Acrylamide is associated with 
adverse effects on testicular function in experimental animals.  
No data regarding these effects in human beings are available. 

    Biological monitoring would be the method of choice in the 
assessment of human exposure to acrylamide, particularly as skin 
absorption is the major route of exposure.  So far, no such 
method has been devised, though results of experimental animal 
studies indicate that the level of acrylamide bound to 
erythrocytes in blood is a measure of the absorbed dose. 

    The most suitable method for the early assessment of adverse 
effects in human beings exposed to acrylamide is the 
electrophysiological examination of peripheral nerves, such as 
measurements of both sensory and motor nerve action potential 
amplitudes and electromyography (EMG).  The sensitivity of this 
method is strongly enhanced if pre-exposure baseline measurements 
have been performed.  Quantitative assessment of vibration 
sensation offers considerable promise as a sensitive and easily 
applicable method.  The results of experimental animal studies 
indicate that other electrophysiological procedures or parameters 
such as sensory and visual evoked potentials may also be useful. 

    Exposure of the environment to acrylamide is mainly limited 
to the contamination of water.  Grouting operations may 
contaminate drinking-water supplies.  Special precautions must 
therefore be taken to limit ground water contamination and, where 
necessary, to prevent its use as drinking-water.  Effluents from 
industries producing or using polyacrylamide, communal sewage 
plants, and from waterworks may also contaminate drinking-water 
supplies, if they are taken from polluted water sources.  The 
current limit for the acrylamide content of drinking-water in 
many countries is 0.25 g/litre.  The acrylamide content of 
drinking-water can be maintained at an acceptable level by 

limiting the amount of acrylamide monomer in the polyacrylamide 
used for water treatment to 0.05%.  Under exceptional conditions, 
swimming in water close to industrial effluents containing 
acrylamide may present a hazard. 

    Preventive measures, such as the enclosure of production 
procedures and the wearing of protective clothing, should be used 
to prevent occupationally-exposed workers absorbing more than 
0.012 mg/kg body weight per day.  The concentration in the 
workroom air should not exceed 0.1 mg/m3.  Ventilated face masks 
may be used to prevent inhalation of acrylamide.  It is possible 
that underlying neurological disease and/or the administration of 
neuroactive drugs might alter human sensitivity to acrylamide 
but, in the absence of definite evidence that this has occurred, 
no specific recommendations can be made. 

1.2.  Recommendations for Further Research

1.2.1.  Analysis

    A method for the determination of acrylamide, bound to 
haemoglobin in red blood cells, should be devised to provide a 
means for the biological monitoring of human exposure to 
acrylamide.  No methods for assessing the concentration of 
acrylamide metabolites in urine are available; such analyses 
would be useful for the assessment of recent exposure, and 
methods should be devised. 

1.2.2.  Exposure

    The development of biological monitoring methods would be 
useful in the routine screening of occupationally-exposed 

1.2.3.  Metabolism and indicators of exposure

    To evaluate fully the health effects and risks associated 
with acrylamide exposure, it is important to elucidate the 
mechanism of neurotoxicity.  Both the proximal toxic agent and 
the primary biochemical lesion need to be identified.  Studies 
should be carried out to investigate further the relationship 
between the concentration of the toxic moiety in the central 
nervous system and possible indicators of exposure, such as the 
concentration of erythrocyte-bound acrylamide or metabolites in 
the urine. 

1.2.4.  Effects

    Further studies on animals are required to establish the no-
observed-adverse-effect levels for morphological changes in the 
central nervous system and to assess the carcinogenic potential 
of acrylamide. 

    Provided that methods for the biological monitoring of 
acrylamide exposure can be devised, epidemiological studies 
should be performed to relate exposure to both neurological 
effects and to the incidence of cancer in acrylamide-exposed 
workers.  Electrophysiological methods, such as the measurement 
of visual and sensory-evoked potentials, that have proved to be 
useful in experimental animal studies, should be evaluated in 
human studies.  More experience is needed in assessing the 
sensitivity and value of quantitative sensory testing.  Further 
studies should be performed to design suitable procedures for the 
health monitoring of an occupationally-exposed population.  
Further animal studies are needed on the effects of acrylamide on 
the developing nervous system and the process of ageing. 


2.1.  Identity

Chemical structure:         H   H   O   H
                            |   |   ||  |
                            C = C - C - N
                            |           |
                            H           H

Chemical formula:           C3H5NO

Synonyms:                   acrylic amide, akrylamide, propen-
                            amide, propenoic acid amide

CAS registry number:        79-06-1

RTECS registry number:      AS 3325000

Relative molecular mass:    71.08

2.2.  Chemical and Physical Properties

    Acrylamide is a white, odourless, crystalline solid that is 
highly soluble in water and reacts through its amide group or 
double bond.  Reactions of the amide group include hydrolysis, 
dehydration, and alcoholysis.  The Diels-Alder reaction, 
polymerization, and the addition of nucleophilic reactants across 
the conjugated ethylenic bond are characteristic reactions.  The 
chemical is stable in solution at room temperature and does not 
polymerize spontaneously.  Commercial solutions of the monomer may 
be stabilized with hydroquinone, t-butylpyrocatechol,  N-phenyl-2-
naphthylamine, or other antioxidants (Windholz et al., 1976).  In 
addition to carbamoylethylation and hydrolysis to acrylic acid, 
acrylamide readily undergoes polymerization and copolymerization 
resulting in a highly cross-linked insoluble gel.  The physical 
properties of acrylamide are summarized in Table 1. 

    Polyacrylamide is a white, odourless solid, soluble in water, 
insoluble in solvents such as methanol, ethanol, and hexane, and 
at least 1% soluble in glycerol, ethyl acetate, glacial acetic 
acid, and lactic acid.  The polymer is safe in relation to both 
fire and explosion (Bikales, 1973).  Levels of residual 
acrylamide monomer in polyacrylamide range from 0.05 to 5%, 
depending on the intended use of the product (Croll et al., 

    The level of residual acrylonitrile monomer in polyacrylamide 
has been estimated to be approximately 1 mg/kg (1 ppm).  In 
addition to polyacrylamide,  N-hydroxymethylacrylamide and 
 N,N'-methylenebisacrylamide are produced commercially from 
acrylamide.  The levels of residual acrylamide in these products 
are not known. 

Table 1.  Physical properties of acrylamide
Appearance                          white crystals

Relative molecular mass             71.08

Melting point                       84.5  0.3 C

Vapour pressure                     0.009 kPa at 25 C
                                    0.004 kPa at 40 C
                                    0.09 kPa at 50 C

Boiling point                       87 C at 0.267 kPa
                                    103 C at 0.667 kPa
                                    125 C at 3.33 kPa

Heat of polymerization              19.8 Kcal/mole

Density                             1.122 g/cm at 30 C

Solubility in g/litre               acetone             631
 solvent at 30 C                   benzene             3.46
                                    chloroform          26.6
                                    ethanol             862
                                    ethylacetate        126
                                    n-heptane           0.068
                                    methanol            155
                                    water               2155
Conversion factor

1 ppm acrylamide in air = 5 mg/m3
Adapted from:  Bikales (1973).

2.3.  Sampling and Analytical Methods

    A number of sampling methods have been devised for 
acrylamide, though no one technique has proved suitable for 
collecting both aerosol and vapour.  A portable pump with a 
membrane filter has been used to collect samples of acrylamide 
aerosol, and midget fritted glass bubblers have been used for the 
determination of acrylamide vapour in air.  Silica-gel sampling 
tubes with membrane filters and midget impingers have been used 
to collect both dust and vapour, the use of midget impingers 
being more efficient than sampling tubes for vapour collection.  
However, a method for sampling gaseous acrylamide using a 
specially-designed sampling tube packed with Flucin-F as the 
solid absorbent has been reported (Suzuki & Suzumura, 1977). 

    A variety of methods has been reported in the literature for 
determining levels of acrylamide in environmental media and 
biological tissues.  Those shown in Table 2 represent the most 
sensitive and/or most widely-used methods.  Acrylamide reacts 
with diazomethane in methanol-ether solution to form a pyrazoline 
derivative that can react with 4-dimethylaminocinnamaldehyde to 

form a brightly coloured (purple) Schiff base complex (Mattocks, 
1968).  This reaction is not specific for acrylamide and is 
insufficiently sensitive for determination in environmental 

    Acrylamide can be converted to its 2,3-dibromopropionamide 
derivative for use with the electron capture detector (ECD).  For 
waste water, as little as 0.1 g acrylamide/litre (as its 2,3-
dibromopropionamide derivative) has been detected by this method 
(Croll & Simkins, 1972).  The detection limit for biological 
samples was 20 g/litre in a biological extract of 0.5 ml (Poole et 
al., 1981).  Levels of 0.1 mg acrylamide/kg (0.1 ppm) in polymer or 
impinger samples (Skelly & Husser, 1978) and 0.2 g/litre (as the 
2,3-dibromopropionamide derivative) in natural and polluted water 
samples (Brown & Rhead, 1979) can be determined by means of the UV 
detection of acrylamide after separation by high-performance liquid 
chromatography (HPLC).  Differential pulse polarography can be used 
to determine acrylamide residues in polyacrylamide with a detection 
limit of less than 1 mg/kg (1 ppm) (Betso & McLean, 1976).  Dust 
and airborne samples (collected by particle and vapour filtration 
in a water impinger) have also been analysed by this technique with 
a reported sensitivity of 0.5 g/litre in the final extract (NIOSH, 

    The gas chromatography (GC) method using the 2,3-
dibromopropionamide derivative and the selective and sensitive 
ECD are the most suitable for trace level determination of 
acrylamide in environmental and biological samples though, for 
the analysis of water samples (natural and polluted), the assay 
of the derivative by HPLC has several advantages over ECGLC.  
These include the suitability for routine analysis, speed of 
determination, and stability of the calibration curve using 
different UV lamps and columns (Brown & Rhead, 1979). 

    Methods for determining impurities found in commercial 
acrylamide (acrylate, ammonium salts, acrylonitrile, 
nitrilotrispropionamide, and butanol insolubles) have been 
described by Norris (1967). 

Table 2.  Analytical techniques for determining acrylamide concentrations in environmental media and 
biological tissues
Technique         Sensitivity     Application                  Comments                   Reference       
Titration         precision       assay of commercial          interference by acrylic    Norris (1967)   
 (bromate-         0.3%          product (sales               acid, ethyl acrylate,                      
 bromide method)                  specification)                N,N'-methylene-bis-                     
Bromination/elec- 5 g/m3         determination of             no interference reported;  NIOSH (1976)    
 tron capture gas                 acrylamide vapour in air     conversion efficiencies                      
 chromatography                                                from monomer to brominated                   
                                                               derivative unknown                            
Flame ionization  0.05 - 5 mg/m3  determination of             using sampling tube        Suzuki &           
 detector; gas    (0.01 - 1 ppm)  acrylamide vapour in air     packed with Flusin-F       Suzumura (1977)    
 chromatography                                                treated with phosphoric                       
 (FID/GC)                                                      acid), the recovery of                             
                                                               acrylamide = 82 - 86%

High-performance  0.1 mg/kg       (a) determination of acryl-  no prior separation of     Skelly & Husser         
 liquid chroma-   (0.1 ppm)       amide monomer in polyacryl-  impurities is required;    (1978)                  
 tography                         amide; (b) acrylamide in     recovery of acrylamide                              
 (reverse phase)                  wipe and impinger samples    = 96%                                              
Direct current    optimum range   determination of monomeric   interference by acrylo-    MacWilliams             
 (DC) polaro-     = 0.01 - 0.5%   acrylamide in poly-          nitrile; cationic and      et al. (1965)            
 graphy           (100 - 5000     acrylamide                   anionic species                                    

Differential      < 1 mg/kg       determination of monomeric   interference by acrylo-    Betso & McLean         
 pulse polaro-                    acrylamide in poly-          nitrile, ethyl acrylates,  (1976)                  
 graphy (DPP)                     acrylamides                  cationic and anionic                               
                                                               species; some substituted                         
                                                               acrylamides; recovery of                            
                                                               acrylamide > 90%                                   

Table 2.  (contd.)
Technique               Sensitivity     Application          Comments                    Reference         
Bromination/electron    optimum range   determination        at low concentrations       Croll & Simkins   
 capture-gas chromat-   = 0.1 g/litre  of acrylamide        (> 0.25 g/litre)           (1972)         
 ography                - 1 mg/litre    in water             analytical interferences                    
                                                             must be removed; conversion                 
                                                             to derivative varies with                   
                                                             water quality; recovery of                  
                                                             acrylamide = 34 - 66%                       
Bromination/high-       0.2 g/litre    determination of     interference by natural     Brown & Rhead   
 performance liquid                     acrylamide in        organic compounds;          (1979)          
 chromatography                         natural and          recovery of acrylamide (as                  
 (reverse phase)                        polluted water       derivative) = 70  9%                       
Colorimetry             0.1 g/ml       urine analysis       interference by aldehydes   Mattocks (1968) 
                        (0.1 ppm)                            ketones, pyrroles, indoles,                 
                                                             hydrazines, chromatic                       
Bromination/electron    20 g/litre     determination of     only suitable for           Poole et al.    
 capture-gas chromat-   (corresponding  acrylamide in        measuring unbound (free)    (1981)          
 ography                to a final      biological samples:  acrylamide; recovery of                     
                        derivatized     (a) plasma           acrylamide 80-90% (in the                   
                        extract of      (b) tissue           concentration range 10 -                    
                        0.5 ml from a       homogenates      1000 ppb)                                   
                        0.5 ml tissue                                                                    

    There is no evidence that acrylamide or its commercially 
significant derivatives are directly produced in the environment. 

3.1.  Production Levels, Processes, and Uses

3.1.1.  World production

    Acrylamide was first produced in 1893 in Germany, and 
commercial production began in 1954.  The annual production of 
acrylamide in the USA for 1979, 1980, and 1981 was approximately 
30 000, 35 000, and 37 000 tonnes, respectively.  The estimated 
production of acrylamide in Japan for 1984 was approximately 36 000 
tonnes (Kagaken Kogyo Nippo, 1980).  The Stanford Research 
Institute estimated the total annual production capacity of firms 
manufacturing acrylamide in 1982 to be 63 500 tonnes.  Conway et 
al. (1979) forecast an increase in the level of production over the 
next few years. 

3.1.2.  Production processes

    Acrylamide monomer is produced commercially by either the 
sulfuric acid hydration or the catalytic hydration of 
acrylonitrile.  Since its introduction in the early 1970s, the 
catalytic process has become the preferred process, and has been 
the only process used in the USA since 1981 (US EPA, 1981).  It 
possesses many advantages over the sulfate process in that high-
purity acrylamide is produced (99.5 - 99.9% compared with 98%), 
there are no undesirable by-products, the conversion efficiency 
is greater (97% compared with 80%), and an expensive acrylamide 
purification step is avoided (Conway et al., 1979; US EPA, 1981). 

    In the catalytic process, acrylonitrile is hydrated to 
acrylamide in the following reaction: 

    CH2 = CHCN + H2O ------------> CH2 = CHCONH2
                      70 - 120 C

This is essentially a continuous process in which unreacted 
acrylonitrile is recycled back to the reactor.  Acrylonitrile and 
the catalyst are removed from the product by evaporation and 
filtration, respectively.  The aqueous acrylamide solution 
produced requires no further treatment or purification. 
Polymerization inhibitors are not required at any stage in the 
process (Davis et al., 1976).  A typical 50% aqueous acrylamide 
solution produced by this process contains 48 - 52% acrylamide 
and a maximum of 0.05% of polymer (ECT, 1978).  Residual 
acrylonitrile has been reported at levels between 1 and 100 mg/kg 
(i.e., up to 0.01%) (US EPA, 1980a). 

    Although monomer manufacture does not generate large volumes 
of by-products, acrylamide-containing waste streams are generated 
during polyacrylamide production (Conway et al., 1979). 

3.1.3.  Uses

    The major use of acrylamide and its derivatives is in the 
production of polymers and copolymers for various purposes. In 
the USA, the only large-scale use of acrylamide, other than in 
the manufacture of polymers, is as a chemical grout; this 
consumed 1100 tonnes (3%) of domestically-produced monomer in 
1980 (US EPA, 1980a).  The relative amounts of acrylamide used in 
water treatment may vary from country to country.  The various 
uses of acrylamide monomer, domestically produced and imported, 
are summarized in Fig. 1. 


    Polyacrylamides are used as flocculents to separate solids 
from aqueous solutions in mining operations, in the disposal of 
industrial wastes, and in the purification of water supplies 
(Tilson, 1981).  The largest market for acrylamide polymers is in 
the treatment of sewage and wastewater (40% of total acrylamide 
production in 1973 in the USA) (Blackford, 1974). 

    Numerous derivatives of acrylamide appear in the literature.  
The two most commercially important are  N-hydroxymethyl-
acrylamide and  N,N-methylenebisacrylamide.  N-hydroxymethyl-
acrylamide is used in the textile industry as a cross-linking 
agent and  N,N-methylenebisacrylamide is used mainly as a 
copolymer in acrylamide grout and in the manufacture of 
photo-polymer printing plates.  Some of the minor uses of 
polyacrylamides are summarized in Table 3. 

Table 3.  Minor uses of polyacrylamides
Coal dust loss preventative            Pigment-binding resins
Coal floatation                        Polyester laminating resins
Dental fillers                         Printing pastes
Drilling fluid additives               Propellant binders
Elastomer curing agent                 Rodent repellents
Electro-refining                       Shaving creams
Emulsion stabilizers                   Soil stabilizers
Flooding agents for petroleum          Suspending agents
 recovery                              Textile resins for warp sizing,
Hair sprays                             printing, shrinkproofing, anti-
Ion-exchange polymers                   static treatments, binding non-
Leather-treating agents                 woven fabrics, improving dye
Moulding resins to increase             receptivity, increasing dimen-
 strength, raise softening temp-        sional stability of viscose
 erature, or to serve as plasti-        rayon
 cizing components                     Thickening agents
Paper additives and resins for         Gel electrophoretic separation
 faster draining, improved filler       of biochemicals
 retention, coating, sizing, wet
 and dry strength improvements
From:  US EPA (1981).

3.2.  Release into the Environment

    Acrylamide monomer may enter the environment from a number of 
sources.  Because closed systems are now used in acrylamide 
manufacture (section 3.1.2), production processes are unlikely to 
be a source of environmental contamination, except in the event 
of a leak from the reactor. 

    Contamination of water by acrylamide, discharged in effluent 
from industries using or manufacturing polyacrylamide, has been 
reported (Croll et al., 1974; Conway et al., 1979; Brown et al., 

    Another potential source is the release of acrylamide monomer 
residues from polyacrylamide flocculents used in processes such 
as sludge or conditioning of oil tailings and clarification of 
waste and drinking-waters.  Croll et al. (1974) demonstrated 
that, in many water-treatment processes, acrylamide is not 
removed (section 4.3). 

    Localized contamination may also arise from the use of 
acrylamide in grouting operations.  The technology exists for the 
 in situ cross-linking of the polymer as opposed to the monomer 
in such operations, thereby decreasing environmental exposure.  
However, it is not known to what extent this technique is 
employed (US EPA, 1980a). 

    Direct contamination from spills and leaks may also occur 
during transportation, storage, use, and disposal of either 
acrylamide or polyacrylamide (Conway et al., 1979). 

    The Dow Chemical Company has estimated that releases of 
acrylamide monomer into the environment during manufacture and 
use could amount to 95 tonnes annually.  A draft report prepared 
for the US EPA estimated a higher figure of 250 tonnes (US EPA, 

3.3.  Disposal of Wastes

    Decontamination of solid and liquid wastes containing 
acrylamide may be achieved by chemical means, e.g., using 
potassium permanganate or ozone (Croll et al., 1974) or by 
biological degradation (Davis et al., 1976; Arai et al., 1981).  
Acrylamide waste may be disposed of by incineration, provided 
nitrogen oxides are scrubbed from flue gases (HBTHC, 1981).  
However, the cost of removing a large percentage of acrylamide in 
waste streams is high. 


4.1.  Transport in the Environment

    Acrylamide and its monomeric analogues have a high mobility 
in an aqueous environment and are readily leachable in soil.  
Acrylamide may travel great distances in the ground water of deep 
rock aquifers, where biodegradability is reportedly absent 
(Conway et al., 1979).  Lande et al. (1979) found acrylamide to 
have a higher mobility (leaching) and lower rate of degradation 
in sandy soils than in clay soils.  Since grouting with acrylamide 
is recommended for sandy soils, a potential hazard for ground water 
contamination may exist.  However, no studies have been made of its 
behaviour in subsurface soil where most grouting applications take 
place.  Acrylamide is unlikely to enter and be distributed in the 
atmosphere to any significant extent, because of its low vapour 
pressure.  Biodegradation is liable to occur to some extent; 
acrylamide should not be regarded as a persistent substance, 
although its rate of degradation may vary with environmental 
conditions (Davis et al., 1976). 

4.2.  Biomagnification and Bioconcentration

    Solubility, partition coefficients, and polarity will affect 
the fate of acrylamide analogues.  Since many acrylamides are 
highly water soluble and are degraded by microorganisms (Brown et 
al., 1980c), it is unlikely that they will bioconcentrate in food 
chain organisms in significant quantities (Metcalf et al., 1973; 
Neely et al., 1974).  Log Po/w (n-octanol/water partition 
coefficient), based on methods of Hansch & Leo (1979), yields an 
approximate value of -1.65 (US EPA, 1980a).  This value indicates 
that the solubility of acrylamide in water is very high compared 
with its solubility in lipids.  Thus, it is considered that 
bioconcentration of organisms in the fatty tissues will be 
minimal.  Similarly, on the basis of its water solubility, 
biomagnification of acrylamide in the food chain is not expected 
(Metcalf et al., 1973). 

4.3.  Transformation

    A wide variety of microbes possess the ability to degrade 
acrylamide (Croll et al., 1974; Lande et al., 1979; Brown et al., 
1980a) under light or dark, anaerobic or aerobic conditions.  
However, periods of several days may elapse prior to any 
significant degradative losses (Conway et al., 1979; Brown et 
al., 1982).  An amidase-producing microorganism belonging to the 
genus  Rhodococcus (strain 10 021R), isolated from the sewage of 
an acrylamide plant, was found to convert acrylamide monomer 
(even in an acrylamide gel stabilizer) into the less toxic 
acrylic acid.  This microorganism was found to be non-virulent in 
experimental animals (even at high doses) and hence, its possible 
use in the control of environmental pollution has been suggested 
(Arai et al., 1981). 

    The residence period of acrylamide may be of the order of 
days, weeks, or months in a river of low microbial activity. 
Brown et al. (1980a) also showed that degradation rates in 
samples of river water, continuously exposed to low levels of 
acrylamide (6 - 50 g/litre), were faster than those in river 
samples not previously exposed.  Acrylamide entering a water 
course may be present for several days (Brown et al., 1980a). 
Under aerobic conditions, acrylamide has been shown to be readily 
degraded in fresh water by bacteria, with a half-life of 55 - 70 
h, after acclimatization of the bacteria to the compound for 33 - 
50 h (Conway et al., 1979).  Half-lives in estuarine or salt 
water are slightly longer (Croll et al., 1974).  Cherry et al. 
(1956) studied the effects of acrylamide (10 mg/litre) on the 
chemical oxygen demand (COD) in filtered river water.  The 
initial half-life was approximately 5 days.  When the samples were 
re-exposed to acrylamide, the COD decreased more rapidly.  Croll et 
al. (1974) monitored the concentration of acrylamide in river water 
containing acrylamide at 8 g/litre.  After a time-lag of 
approximately 100 h, the acrylamide degraded rapidly.  The addition 
of acrylamide at 10 g/litre to natural waters, which had already 
been exposed to acrylamide, resulted in a shorter time-lag and 
faster degradation rates. 

    In laboratory experiments, acrylamide was not adsorbed by 
sewage sludge, natural sediments, clays, peat, or synthetic 
resins over the pH range 4 - 10.  Therefore, removal by this 
means seems unlikely unless converted to a less polar and/or 
charged compound.  Temporary entrainment in a polymeracrylamide-
particle matrix may occur during flocculation processes, and rapid 
leaching will occur should such a matrix remain in contact with 
water for a period of time (Brown et al., 1980c).  Polyacrylamide 
is used for the conditioning of waterworks sludge.  Since 92 - 100% 
of the residual acrylamide in the polymer is leached out in the 
sludge-conditioning process, care must be taken to ensure that any 
conditioned sludge supernatant which is returned to the main flow, 
does not raise the acrylamide concentration in finished water above 
acceptable levels.  A removal rate of 75% was calculated by Croll 
et al. (1974) for an overloaded sewage works receiving an 
acrylamide effluent of 1.1 mg/litre. 

    Lande et al. (1979) found a faster rate of degradation and 
lower mobility of acrylamide in silt clay soils than in clay 
loam, loamy fine sand, or loam.  Acrylamide is recommended for 
grouting on sandy soils, in which it has a relatively low rate of 
degradation and a high mobility.  Unfortunately, no studies have 
been carried out on the behaviour of acrylamide in subsurface 
soil where most grouting applications take place. 

    The half-life of acrylamide in aerobic silt loam was of the 
order of 20 - 45 h at a concentration of 25 mg/kg and a 
temperature of 22 C, and 94.5 h at 500 mg/kg and 20 C. 
Increasing the acrylamide concentration or decreasing the 
temperature increased the half-life (Lande et al., 1979; 
Abdelmagid & Tabatabai, 1982).  The behaviour of acrylamide 

(100 mg/kg) in soil-plant systems was investigated by Nishikawa 
et al. (1979).  Acrylamide decomposed mainly by hydrolysis to 
form acrylic acid.  In upland farming conditions (aerobic 
conditions), there was a rapid decrease in total organic carbon 
(TOC), up to 15 days after application, whereas in wet-land 
(rice) conditions, the decrease was slow.  These fluctuations in 
TOC under both types of farming conditions corresponded closely 
to the changes in TOC originating from acrylamide and acrylic 
acid (Nishikawa et al., 1979). 

    Polyacrylamide may be hydrolysed, but acrylamide monomer is 
not formed in solutions.  Some photosensitized polymerization is 
possible for certain acrylamide derivatives.  However, major 
modification of the molecule as a consequence of 
chemical/photochemical reaction seems unlikely (Davis et al., 


5.1.  Environmental Levels

5.1.1.  Ambient air and soil

    The results of monitoring studies in the USA, performed near 
6 plants producing acrylamide and/or polyacrylamides, showed 
average acrylamide levels in the air of less than 0.2 g/m3, in 
either vapour or particulate form, and less than 0.02 mg/kg (0.02 
ppm) in soil or sediment samples (Going, 1978). 

5.1.2.  Water

    The Committee on New Chemicals for Water Treatment in the 
United Kingdom recommended that:  commercial polyacrylamide used in 
the treatment of drinking-water should not contain more than 0.05% 
acrylamide monomer, the average amount of polymer added to water 
should not exceed 0.5 mg/litre, and the maximum dose should not 
exceed 1.0 mg/litre (UK Ministry of Housing and Local Government, 

    Although limits have been recommended for the amount of 
polyacrylamide used in the clarification of drinking-water, much 
higher levels may be encountered in other uses, where polymers 
with a higher monomer content are used at much higher levels.  
For example, polyacrylamides used for effluent treatment may 
contain monomer levels of between 1 and 50 g/kg (Croll et al., 
1974).  If effluent from such processes were to enter water 
subsequently treated for public supply, then the acrylamide 
concentration derived from the raw water source might be higher 
than that resulting from the clarification process.  The 
acrylamide contents of effluents from several industries using 
polyacrylamide are shown in Table 4. 

    Brown et al. (1980b) did not detect any acrylamide in 
effluents from the china-clay industry, after several months of 
polymer use (analytical detection limit, 0.2 g/litre).  Croll et 
al. (1974) detected 16 g acrylamide/litre in the effluent from a 
clay pit, which resulted in an acrylamide level of 1.2 g/litre in 
the receiving stream.  Further downstream at a waterworks intake, 
this level had dropped to 0.3 g/litre. 

    Environmental monitoring at sites of acrylamide and 
polyacrylamide production in the United Kingdom and the USA 
indicates that levels of acrylamide reaching surface waters from 
industrial effluent would generally be difficult to detect below 
1 g/litre (Croll & Simkins, 1972; Going & Thomas, 1979).  A 
value of 1.5 mg/litre was recorded by Going (1978) in a small 
stream receiving effluent directly downstream from a 
polyacrylamide producing plant in the USA.  High levels have also 
been found in the vicinity of local grouting operations (Croll et 
al., 1974).  Igisu et al. (1975) reported a level of 400 mg 
acrylamide/litre in well-water in Japan that had been 
contaminated from a grouting operation 2.5 metres away. 

Table 4.  Concentrations of acrylamide in some industrial effluents
Effluent                           Acrylamide     Reference            
Colliery A; tailings lagoon         42            Croll et al. (1974)  
Colliery B; tailings lagoon         39            Croll et al. (1974)  
Colliery C; coal washing;           1.8           Croll et al. (1974)  
 effluent lagoon                                                       
Colliery/coking plant effluent      0.74          Croll et al. (1974)  
Paper mill A; treated effluent      0.47          Croll et al. (1974)  
Paper mill B; treated effluent      1.2           Croll et al. (1974)  
Clay pit                            16.0          Croll et al. (1974)  
Paper mill A & B; treated effluent  < 1.0         Brown et al. (1980b) 
Paper mill A & B; process water     < 1.0         Brown et al. (1980b) 
Paper mill C; treated effluent      14.4          Brown et al. (1980b) 
Paper mill C; process water         45.4          Brown et al. (1980b) 

    No acrylamide (detection limit 4 g/litre) was detected in 
process waters from a sewage works, either before or after 
polymer addition (Brown et al., 1980a).  In another works, 
samples of vacuum- and pressure-filtered sewage sludge, 
conditioned with polyacrylamide, were found to contain up to 0.1 
g acrylamide/litre.  On the basis of the acrylamide content and 
polymer dosage, these filtrates would have contained up to 25 g 
acrylamide/litre, had no degradation and/or adsorption occurred 
(Croll et al., 1974). 

    The fate of acrylamide monomer in waterworks sludge 
conditioning (using the polymer) was investigated by Croll et al. 
(1974).  In 2 waterworks, between 74 and 87% of acrylamide 
(residual monomer from the polymer) passed into the recovered 
water.  This water was either returned directly to the waterworks 
intake or disposed of as an effluent.  No acrylamide was detected 
by Brown et al. (1980b) in process waters from a waterworks using 
polyacrylamide for effluent treatment (detection limit 0.2 
g/litre).  The authors also investigated the effects of 
accidental polymer overdosing.  A maximum concentration of 8.6 g 
acrylamide/litre was detected in backwash water, 30 min after 
spiking with 100 times the normal polymer dosage.  The effluent 
was diluted approximately 12 times, in river water 500 metres 
downstream from the discharge (0.7 g/litre).  Such effluents 
from over-loaded water- or sewage sludge-conditioning works could 
present a hazard to water supplies taken downstream of the 
effluent discharge (Croll et al., 1974). 

5.1.3.  Food

    The US Food and Drug Administration has established a maximum 
acrylamide residue level of 0.2% (2 g/kg) for acrylamide polymers 
used in paper or paperboard in contact with foodstuffs (Bikales, 
1973).  Similarly, in the Federal Republic of Germany, the 
Federal Health Authority have recommended that the level of 

polyacrylamide used as an agent for retention (Table 3) in 
foodstuff packaging should not exceed 0.3%.  This should not 
include more than 0.2% monomer.  The use of polyacrylamides in the 
washing of pre-packed foods and vegetables and the clarification 
and stabilization of wines has been described (MacWilliams, 1973; 
Croll et al., 1974).  In the USA, polyacrylamide used in the 
washing of fruits and vegetables must not contain more than 0.2% (2 
g/kg) acrylamide monomer (IRPTC, 1983).  No data regarding the 
levels of acrylamide in foods or the potential effects that such 
contamination might have on the environment are available.  Brown 
et al. (1980b) mentioned the possibility of acrylamide consumption 
by farm animals, via feed containing industrial or sewage sludges. 

5.2.  General Population Exposure

    The general population is potentially exposed to acrylamide 
by inhalation, skin absorption, water, and by ingestion of food. 

    In the Federal Republic of Germany, the level of residual 
monomer in polyacrylamide used in hair sprays is limited to 0.01% 
(0.1 g/kg)a. 

5.3.  Occupational Exposure

    Information on occupational exposure to acrylamide is sparse.  
In 1976, NIOSH estimated that approximately 20 000 workers might 
be exposed to acrylamide in the USA; however, there is no 
indication that this figure included grouting workers and Conway 
et al. (1979) estimated that this group of workers could number 
at least 2000 by 1980.  A large number of laboratory workers are 
also potentially exposed to acrylamide during the preparation of 
polyacrylamide gels for electrophoresis.  Although exposure 
levels have not been reported for grouters, the potential for 
hazard from this use is probably greater than that from other 
uses because of the uncontrolled nature of the grouters' 

    No epidemiological studies are available, and only limited
air monitoring data (Vistron Company, USA), on acrylamide
concentrations in the workplace.  Stationary air sampling
showed acrylamide concentrations ranging from 0.1 to 0.4 mg/m3
for a control room, from 0.1 to 0.9 mg/m3 for a bagging room,
and from 0.1 to 0.4 mg/m3 for a processing area.  The sampling
was performed during an 8-h working day, and the values cited
represented weekly averages.  In another factory in the USA,
personal sampling (4 h) revealed acrylamide exposure levels of
0.76 mg/m3 and 0.52 mg/m3 for 2 packers, 0.48 mg/m3 for a
reactor operator, and 0.52 mg/m3 for a dryer operator (NIOSH,
1976).  In another factory, both personal sampling and stationary
sampling were performed during 1974-75.  Personal sampling
concentrations ranged from 0.1 to 3.6 mg/m3, with the highest
concentrations seen in the bagging area.  The median value for
all personal monitoring data was 0.6 mg/m3, while the stationary
a   Bundesministerium fr Jugend, Familie und Gesundheit, 1984.

sampling showed concentrations ranging from 0.1 to 0.3 mg/m3.
Thus, in 2 factories, the personal sampling measurements were
between 2 and 3 times higher than stationary sampling measurements
(NIOSH, 1976).

    A recommended threshold limit value/time-weighted average
(TLV/TWA) for acrylamide in workroom air is 0.3 mg/m3 and the
short-term exposure limit (TLV-STEL) is 0.6 mg/m3 (ACGIH,
1984).  Other recommended occupational exposure levels (for
acrylamide in workroom air) for various countries are shown in
Table 5.

Table 5.  Occupational exposure levels for acrylamide in workroom 
air of various countriesa
Country               Exposure limit   Category of   Notation
                      (mg/m3)          limitb 
Australia             0.3              TWAc          Sd
Belgium               0.3                            S
Finland               0.3              TWA           S
Germany, Federal      0.3              MAKe          Sf
 Republic of
Hungaryg              0.3              TWA
                      1.5              STEL
Italy                 0.3              TWA           S
Japan                 0.3              MACh          S
Netherlands           0.3              TWA           S
Sweden                0.3              TWA           S
                      0.9              STELi
Switzerland           0.3              MAC           S
United Kingdom        0.3              TWA           S
                      0.6              STEL


 (a) NIOSH/OSHA       0.3              PELj          S
 (b) ACGIH            0.3              TWA           S
                      0.6              STEL

USSRk                 0.2              MAC

Yugoslavia            0.3              TWA           S
a   From:  ILO (1980) and IRPTC (1983).
b   Category of limit:  broad definition of type of limit stated. 
    For exact meaning of terms, refer to individual country 
c   TWA (time-weighted average):  a mean exposure limit averaged 
    generally over a working day whereby, within prescribed limits, 
    excursions above the level specified are permitted, provided 
    they are compensated for by excursions below the level specified.
d   SI:  specified as a skin irritant.
e   MAK:  maximum worksite concentration.

Table 5.  (contd.)
f   S (skin absorption):  this designation refers to the potential
    contribution of cutaneous absorption either by airborne or, more
    particularly, by direct contact.
g   From:  Hungary, State Ministry of Health (1978).
h   MAC:  maximum allowable concentration.
i   STEL (short-term exposure limit):  a maximum concentration 
    allowed for a short specified duration.
j   PEL:  permissible exposure limit.
k   From:  USSR, Ministry of Health (1979).

Note:   Occupational exposure levels and limits are derived in 
        different ways, possibly using different data and expressed 
        and applied in accordance with national practices.  These 
        aspects should be taken into account when making comparisons.


6.1.  Experimental Animal Studies

6.1.1.  Absorption and distribution

    Acrylamide has been reported to induce neurotoxic effects in 
many animal species following absorption via the respiratory, 
dermal, and oral routes (Hamblin, 1956).  The absorption and 
distribution of acrylamide applied dermally to rabbits was 
studied by Hashimoto & Ando (1975).  A single 30-min application 
of a 10 - 30% aqueous solution of [1-14C]-acrylamide rapidly 
penetrated the skin (auto-radiography showed a concentration of 
14C in the hair follicles) and appeared in the blood in 2 forms, 
mainly protein-bound, and in a free water-soluble form.  About 
50% of the radioactivity in the blood was associated with the 
protein-bound fraction, 24 h after cessation of contact.  This 
value increased to about 90%, when there was daily contact with 
acrylamide (30-min duration) for 7 days.  Similar patterns of 
distribution were observed after intravenous (iv) administration.  
In rats, Hashimoto & Aldridge (1970) found that the highest 
levels of radioactivity after a single iv dose (100 mg/kg body 
weight) were in whole blood.  After 24 h, the plasma contained 
little radiolabel and  in vitro binding to haemoglobin was 
demonstrated; this suggested that the protein-bound radioactivity 
in the blood was associated with the red blood cells.  By 14 
days, the majority of free/soluble radiolabel had disappeared in 
both blood and tissues.  However, the protein-bound radiolabel 
remained at 100% and 25% of the 24-h levels in blood and tissues, 
respectively.  During the 48 h following an iv dose of [1,3-14C]-
acrylamide at 50 mg/kg (Young et al., 1979), the concentration of 
radiolabel decreased in selected rat tissues but increased in red 
blood cells to a plateau that was between 10 and 90 times higher 
than the levels in the other tissues examined. 

    Miller et al. (1982) determined the extractable fraction of 
parent acrylamide in tissues obtained from rats, at various time 
intervals after an iv dose of [14C]-acrylamide at 10 mg/kg body 
weight.  Values, which ranged from 85 to 100% at 15 min, 
decreased as time progressed (10 - 50% at 12 h and less than 1% 
after 24 h).  The extractable fraction from the blood was only 
50% at 15 min and less than 1% at 12 h.  Covalent binding of 
acrylamide to cysteine residues in rat haemoglobin was 
demonstrated by Hashimoto & Aldridge (1970) and binding occurred 
at the 4 active sulphydryl groups in the haemoglobin molecule. It 
seems likely that the non-extractable fraction  in vivo is due to 
this reaction or its metabolites.

    The only biological component that has substantial irreversible 
binding and has been found to concentrate acrylamide (as 14C) is 
the red blood cell.  Pastoor & Richardson (1981) found that 3 h 
after iv administration to rats, uptake of acrylamide by red blood 
cells was essentially complete and had plateaued.  The plateau 
level was closely correlated with dose (r2 = 0.995) and was 
determined to be 2.0  0.2% of the dose per ml of red blood 

cells.  After iv administration of 10 mg [14C]-acrylamide/kg body 
weight, the binding to erythrocytes in rats plateaued at 12% of 
the dose and accounted for essentially all of the 14C in the 
blood (Miller et al., 1982).  When acrylamide was given to rats 
(30 mg/kg body weight per day), the blood concentration rose to a 
plateau of about 400 mg/kg, on day 9 (Young et al., 1979). 

    Measurements of unbound acrylamide in the blood of rats given 
a single iv dose indicated that acrylamide is distributed 
throughout total body water within 30 min (Edwards, 1975a).  
Fetal absorption of acrylamide has been reported in various 
mammalian species demonstrating the permeability of the placenta 
(section 7.5) (Edwards, 1976a; Ikeda et al., 1983).  Miller et 
al. (1982) studied the distribution and fate of orally-
administered [14C]-acrylamide (10 mg/kg body weight) in rats.  
An absorption phase, which had peaked by the end of the first 
hour, was observed in liver, fat, kidney, and testis.  Acrylamide 
is highly soluble in water and poorly soluble in lipids.  
Concentration in particular tissues is due, either to covalent 
binding to particular proteins, or to an accumulation of 
metabolites, e.g., in the liver and kidney.  The concentration of 
radiolabel in neural tissue (brain, spinal cord, and sciatic 
nerve) did not differ significantly from that in non-neural 
tissue, except for that in red blood cells (Poole et al., 1981; 
Miller et al., 1982).  Ando & Hashimoto (1972) reported that the 
distribution of radiolabel in the sciatic nerve was 2.5 times 
greater in the distal half of this tissue.  Acrylamide has also 
been reported to concentrate in the sciatic nerve terminals, with 
accumulation taking place directly from the blood stream 
(Hashimoto, 1980).  Hashimoto & Aldridge (1970) detected a 
considerable amount of protein-bound radioactivity in the brain 
and spinal cord of rats, 14 days after a single iv dose (100 
mg/kg body weight) of [14C]-acrylamide.  They suggested that this 
finding could be significant if protein binding were involved in 
the primary lesion. 

6.1.2.  Metabolism

    The biotransformation of acrylamide has been shown to be 
mainly mediated through glutathione conjugation (Pastoor et al., 
1980; Dixit et al., 1981a; Miller et al., 1982).  Studies by 
Dixit et al. (1981a) established that the reaction of acrylamide 
with glutathione occurs by both non-enzymic and enzymic 
(catalysed by glutathione- S-transferase (GST) (EC 
reactions and occurs in both the liver and the brain.  Edwards 
(1975a) demonstrated biliary excretion of a glutathione conjugate 
of acrylamide ( S-beta-propionamido-glutathione) after iv 
administration to rats.  In studies by Miller et al. (1982), 15% 
of the dose (as total 14C) was excreted in the bile within 6 h of 
oral administration to rats; only 1% was parent acrylamide. 

    Miller et al. (1982) detected at least 4 urinary metabolites 
after the oral administration of [14C]-acrylamide to rats.  The 
major metabolite was mercapturic acid ( N-acetyl-cysteine- S-
propionamide), which accounted for 48% of the dose.  Unmetabolized 

acrylamide (2%) and 3 non-sulfur-containing metabolites (total 
14%) were also present in the urine; cysteine- S-propionamide was 
identified as a urinary metabolite by Dixit et al. (1982). 

    Glutathione conjugation is presumed to be a detoxifying 
process, since Dixit et al. (1980a) demonstrated an earlier onset 
of toxicity after depletion of hepatic glutathione stores and 
Edwards (1975b) found that the glutathione conjugate did not 
induce any neurotoxic effects.  Concurrent administration of 
methionine (involved in the synthesis of glutathione) with 
acrylamide has also been shown to reduce the neurotoxic potency 
of acrylamide (Hashimoto & Ando, 1971).  Inhibition of GST by 
acrylamide has been reported by Dixit et al. (1981b), Mukhtar et 
al. (1981), and Das et al. (1982).  Thus, acrylamide may inhibit 
not only its own detoxification, but also that of other toxic 
xenobiotics along this pathway.  Pre-exposure of rats to 
acrylamide has been shown to inhibit the biliary excretion of 
methylmercury, which requires glutathione for its 
biotransformation (Refsvik, 1978). 

    Hashimoto & Aldridge (1970) reported that 6% of an iv dose
of [1-14C]-acrylamide, was exhaled by rats as [14C]-carbon
dioxide (14CO2), for 8 h after administration.  No exhaled
14CO2 was detected by Miller et al. (1982) using
[2,3-14C]-acrylamide.  It would appear, therefore, that
acrylamide is metabolized, to a small extent, by cleavage of
the carbonyl group.  Apparently, the remaining 2-carbon
fragment is not metabolized to carbon dioxide.

    Efforts to demonstrate the role of the microsomal mixed-
function oxidase (MFO) (EC system in the 
biotransformation of acrylamide have not been successful.  There is 
evidence suggesting that, under  in vitro conditions, a reactive 
metabolite of acrylamide is formed by the MFO system, which 
inhibits aniline hydroxylase activity and cytochrome P-450 in rats 
(Ortiz et al., 1981).   In vivo studies by Das et al. (1982) also 
demonstrated a decrease in hepatic MFO enzyme levels.  Similar 
studies on mice by Nilsen et al. (1978) demonstrated a reduction in 
only one form of hepatic cytochrome P-450 (P-45047), without any 
change in the total amount of cytochrome P-450.  A reduction in 
both cutaneous and hepatic aryl hydrocarbon hydroxylase (AHH) 
activity was observed in mice following topical application of 
acrylamide (Mukhtar et al., 1981).  Edwards et al. (1978) reported 
a 15% depletion of microsomal cytochrome P-450 in rats after a 
single subcutaneous (sc) dose of acrylamide. This observation was 
accompanied by a 100% increase in liver porphyrins; there is 
evidence that reactive metabolites of allyl groups formed via 
cytochrome P-450 are responsible for the abnormal degradation of 
haem (Ortiz de Montellano & Mico, 1980). 

    SKF 525A is an inhibitor of hepatic mixed-function oxidases 
(decreased detoxification or bioactivation) while phenobarbital 
increases them (increases bioactivation and/or detoxification) 
and also induces glutathione  S-transferases (detoxification).  
Kaplan et al. (1973) reported that pretreatment of rats with SKF 

525A, to inhibit hepatic mixed-function oxidase activity, 
enhanced the neurological effects and lethality of acrylamide.  
On the other hand, acrylamide-induced changes in striatal 
dopaminergic receptors were completely prevented by SKF 525A 
(Agrawal et al., 1981a).  With regard to the effects of hepatic 
microsomal inducers on the development of acrylamide neuropathy, 
Kaplan et al. (1973) reported a significantly delayed onset of 
ataxia after ip administration of acrylamide following 
pretreatment of rats with phenobarbital (or DDT), while Edwards 
(1975b) failed to obtain similar results after oral 
administration.  Hashimoto & Tanii (1981) reported that 
phenobarbital treatment reduced neuro- and testicular toxic 
effects due to acrylamide, or selected analogues in mice.  
However, Kaplan et al. (1973) found that the delayed onset of 
neurotoxicity was accompanied by a greater degree of peripheral 
nerve injury in pretreated animals.  In studies by Tanii & 
Hashimoto (1981), phenobarbital pretreatment did not increase the 
rate of  in vitro metabolism of acrylamide, but increased the 
rate of reaction of acrylamide with glutathione by some 40%.  
Because it has not yet been established whether the biological 
effects of acrylamide are due to the parent compound or to a 
bioactivated derivative, it is difficult to interpret the results 
of these studies. 

6.1.3.  Elimination and excretion  Elimination

    Acrylamide (as total 14C) was eliminated from rat tissues
in a biphasic manner (Miller et al., 1982).  In the first 
component, the elimination half-life in most tissues was less 
than 5 h and, in the second, 8 days or less.  Testes and skin had 
slower elimination rates with initial half-lives of 8 and 11 h, 
respectively.  An interesting observation was that the 
elimination of radiolabel in neural tissue did not differ 
significantly from that in non-neural tissue. 

    The amount of 14C in blood remained constant at 12% of the 
dose for up to 7 days.  However, 14C in plasma was eliminated 
very rapidly.  The terminal elimination half-life for acrylamide 
in blood (as 14C) was reported by Pastoor & Richardson (1981) to 
be about 10 days, which is close to the figure of 13 days 
suggested by Hashimoto & Aldridge (1970). 

    In contrast to the kinetics for total 14C, the elimination of
parent acrylamide fitted a monoexponential curve.  The half-life 
of parent acrylamide in blood was 1.7 h (Miller et al., 1982), 
which is comparable with the figure of 1.9 h reported by Edwards 
(1975a).  Pastoor & Richardson (1981) estimated that the half-
life of plasma acrylamide was approximately 2.5 h.  They also 
observed that the semi-log plasma elimination curves became more 
linear as the dose increased from 2 to 20 mg/kg body weight (iv 
administration), which implied a saturation of elimination 
pathways at higher doses.  The elimination of parent acrylamide 

from tissues corresponded with that seen in the blood.  Within 24 
h, no detectable levels were found in any tissue (Miller et al., 
1982).  The conclusion is that the half-life for parent 
acrylamide in blood and tissues makes it unlikely that this form 
accumulates in the body.  Excretion

    The excretion half-life of parent acrylamide in rat urine
was 7.8 h (Miller et al., 1982) (section 6.1.1).  Using
[1-14C]-acrylamide, Hashimoto & Aldridge (1970) reported that
approximately 6% of the dose was exhaled as 14CO2.  In an
extensive study of the kinetics of both orally- and iv-administered 
[2,3-14C]-acrylamide, it was shown that the rate of elimination 
of the radiolabel in urine was independent of the route of 
administration.  Within 24 h, about two-thirds of the dose was 
excreted in the urine and three-quarters in 7 days.  Faecal 
excretion was small (4.8% in 24 h and 6% by 7 days).  Since 15% 
of the dose appeared in the bile within 6 h, acrylamide or its 
derivatives must undergo enterohepatic circulation.  Thus, 
approximately 80% of the radiolabel was excreted within 7 days 
and, of this, a very large proportion (90%) was in the form of 

    When [14C]-acrylamide was given to rats daily by gavage or
in the drinking-water at 30 mg/kg body weight per day, the daily 
excretion of radioactivity in the urine was nearly constant 
during the 14-day period (Young et al., 1979), most of the dose 
being excreted as 2 major metabolites together with a small 
amount of the parent compound.  Miller et al. (1982) reported 
that the excretion rates of radiolabel in urine, following 
administration of 1 - 100 mg acrylamide/kg body weight were 
independent of dose, implying zero order elimination kinetics.  
Excretion of both free and protein-bound [14C] acrylamide has 
been demonstrated in the milk of rats, during lactation (section 
7.5) (Walden & Schiller, 1981). 

6.2.  Human Studies

    Limited data are available on absorption, distribution, 
elimination, and metabolism in human beings, and these have 
mainly been derived from clinical observations in cases of 
poisoning.  The findings in animal studies that acrylamide is 
readily absorbed, whatever the route of exposure, is supported by 
clinical observations.  The majority of human cases of acrylamide 
poisoning reported in the literature have occurred through skin 
absorption (Fujita et al., 1961; Auld & Bedwell, 1967; Garland & 
Patterson, 1967; Morviller, 1969; Graveleau et al., 1970; 
Takahashi et al., 1971; Cavigneaux & Cabasson, 1972; Davenport et 
al., 1976; Mapp et al., 1977).  Poisoning by ingestion of 
contaminated water has also been reported (Igisu et al., 1975), 
indicating efficient gastrointestinal absorption of acrylamide.  
However, quantitative data on absorption or excretion in human 
beings are not available at present.  There are no methods for 

determining acrylamide or its metabolites in blood or excreta, 
and such methods are urgently needed.  Animal data suggest that 
the concentration of acrylamide in red blood cells might serve as 
an index of body burden of acrylamide (Edwards, 1976b; Pastoor & 
Richardson, 1981).  However, no studies are available on the 
relationship between the blood concentration of acrylamide and 
its toxic effects or on human urinary excretion of acrylamide and 
its metabolites. 


7.1.  Neurological Effects

    Regardless of species, nearly all studies on acrylamide 
intoxication involve manifestations of various degrees of 
neurotoxicity; however, it must be emphasized that polyacrylamide 
itself is not neurotoxic.  Some effects of acute acrylamide 
intoxication are shown in Table 6.  Results of experimental 
animal studies suggest that central nervous system (CNS) effects 
predominate in acute acrylamide poisoning, whereas, on repeated 
administration of divided doses, signs of peripheral neuropathy 
become more evident (Le Quesne, 1980).  The general toxicological 
profile of poisoning, following prolonged exposure to repeated 
doses, includes tremors, incoordination, ataxia, muscular 
weakness, distended bladder, and loss of weight.  In acute 
single-dose studies on cats, Kuperman (1958) described ataxic 
tremors together with severe tonic-clonic convulsions and other 
signs of diffuse central excitation.  With prolonged intoxication 
in cats, incoordination was the first malfunction observed, 
followed by limb weakness (McCollister et al., 1964; Le Quesne, 
1980).  The development of neuropathy usually begins with the 
involvement of the distal parts of limbs and slowly progresses to 
the proximal regions of the body. 

7.1.1.  Neurobehavioural effects

    Numerous investigators have used neurobehavioural techniques 
to detect and quantify the neurotoxic effects of acrylamide, 
including effects on motor and sensory function, on-going 
performance, and cognitive processes. 

    The procedures and the effects of acrylamide on neuromotor 
function in rats are listed in Table 7 according to sensitivity, 
i.e., the lowest cumulative dose required to produce a 
significant alteration.  Motor dysfunction, as measured by 
impaired rotarod performance, hind-limb splay, and hind-limb 
weakness, can be observed in the dose range 100 - 320 mg/kg.  In 
other procedures involving a conditioned motor response, such as 
food-reinforced, schedule-controlled behaviour (VI or FR), changes 
in performance have been observed in the dose range 25 - 75 mg/kg. 
Tilson et al. (1979) associated neuromuscular weakness with 
histopathological alterations, i.e., loss of fibres and axonal 
swelling in peripheral nerves, both during dosing and following 
cessation of exposure.  Other studies with mice have also shown 
that motor dysfunction can be quantified using neurobehavioural 
procedures that assess motor coordination and neuromuscular 
strength (Gilbert & Maurissen, 1982; Teal & Evans, 1982). 

Table 6.  Clinical signs of acute acrylamide intoxication in mammals
Species      Route     Dose         Mortality  Clinical signs                       Reference
                       body weight) 
Mouse        oral      100 - 1000   -          postural and motor incoordination;   Kuperman (1957)
                                               convulsions; death
Mouse        dermal    (40% sol.)   100%       50% mortality within 45 min          Novikova (1979)
Rat          oral      100 - 200    -          tremor; general weakness; death      Fullerton & Barnes
Rat          ip        100 - 1000   -          ataxia; general weakness; death      Kuperman (1958)
Rat          oral      126          0/5        slight weight loss; coma             McCollister et al.
Rat          oral      256          5/5        death within 24 h                    McCollister et al.
Guinea-pig   oral      126          1/4        tremors; pupil dilation              McCollister et al.
Guinea-pig   oral      252          4/4        death within 24 h                    McCollister et al.

Table 6. (contd.)
Species      Route     Dose         Mortality  Clinical signs                       Reference
                       body weight) 
Rabbit       sc        500          -          postural and motor incoordination;   Kuperman (1957)
                                               convulsions; death
Rabbit       oral      63           0/4        slight weight loss                   McCollister et al.
Rabbit       oral      126          1/4        tremors; pupil dilation              McCollister et al.
Rabbit       oral      252          4/4        death within 24 h                    McCollister et al.
Rabbit       dermal    500 - 1000   1/5        oedema; death                        McCollister et al.
Cat          iv or ip  65 - 70      -          postural and motor incoordination    Kuperman (1957)
Cat          iv        5000         -          general weakness; circulatory        Kuperman (1957)
                                               collapse; death
Cat          ip        100          -          unconsciousness after 24 h; severe   McCollister et al.
                                               effects or death                     (1964)
Dog          oral      100          -          convulsions; postural and motor      Kuperman (1957)
Table 7.  Summary of effects of acrylamide on motor function of rats
Test                 Route        Least effective    Reference
                                  cumulative dose   
Taste aversion       oral         10                 Anderson et al.
Food-reinforced      gavage       25                 Tilson & Squibb
 variable-interval                                   (1982)
 (VI) responding                                                
Open-field           ip           50                 Gipon et al.
 rearing                                             (1977)
Altered gait         ip           50                 Jolicoeur et al.
Food-reinforced      gavage       75                 Tilson et al.
 fixed-ratio (FR)                                    (1980)
Horizontal motor     ip           100                Gipon et al.
 activity                                            (1977)
Hind-limb            gavage       100                Tilson & Cabe
 weakness                                            (1979)
Hind-limb splay      ip           150                Edwards &
                                                     Parker (1977)
                     ip           200                Jolicoeur et al.
                     (oral)       280                Edwards &
                     diet                            Parker (1977)
Rotarod              ip           300                Gipon et al.
                     ip           320                Kaplan & Murphy
                                                     (1972); Kaplan
                                                     et al. (1973)
Inclined board       gavage       500                Fullerton &
                                                     Barnes (1966)
Running wheel        (oral)       550                Lewkowski et al.
 activity            diet                            (1978)
Motor activity       gavage       600                Tilson et al.
 (automex)                                           (1979)

    Responses associated with appetitive and/or consummatory 
behaviour have also been used to quantify acrylamide-induced 
toxicity.  Teal & Evans (1982) found that administration of 
acrylamide for 30 days produced a considerable increase in 

periodic milk-licking, even in severely intoxicated animals. 
These effects are presumed to be associated with disturbances in 
water balance (Gipon et al., 1977) and may be associated with 
alterations in thirst and hunger regulation in the hypothalamus. 

    Blunting of tactile sensitivity is recognized as an early 
effect following exposure to acrylamide; such sensory signs 
usually precede motor involvement.  Recently, Maurissen et al. 
(1983) used operant psychophysical techniques to assess vibratory 
or electrical stimuli applied to the fingertips. Monkeys dosed 
orally with 10 mg/kg acrylamide, 5 days per week, for up to 9 
weeks, were found to exhibit impaired vibration sensitivity 
before the onset of neuromuscular effects.  Sensory effects were 
evident for several months after dosing ceased.  Sural nerve 
biopsies did not reveal a clear association between loss of nerve 
fibres and degree of sensory loss.  These and other data suggest 
that vibration sensory loss is probably due to dysfunction of the 
end-organ receptors.  Spencer & Schaumburg (1977) reported that 
the generator potential of the Pacinian corpuscle was decreased 
by acrylamide exposure at a time when pathology was not evident. 

    Maurissen et al. (1983) also found that sensitivity to the 
electrical stimulus did not change, suggesting that acrylamide 
differentially affected the mechanoreceptors.  Studies on rats 
have shown that acrylamide does not markedly affect 
responsiveness to thermal stimuli, even when motor dysfunction is 
present (Pryor et al., 1983). 

    Anderson et al. (1982) studied the effects of acrylamide on 
conditioned taste aversion, considered to be due to interoceptive 
effects discernible by the animal.  Taste aversion was observed 
following a single dose of acrylamide given by gavage, suggesting 
that acrylamide can induce effects at doses much lower than those 
required to induce neurohistopathological changes, and the 
neurological substrates or processes involved may be different 
from those mediating the expression of central peripheral distal 

    Where animals survived the effects of acute poisoning, 
recovery was usually rapid and complete (Spencer & Schaumburg, 
1974b).  Similarly, after long-term poisoning, neuropathy was 
reversible, though recovery was often slow (McCollister et al., 
1964; Hopkins & Gilliatt, 1971). 

7.1.2.  Electrophysiological effects  Peripheral effects

    Various electrophysiological parameters have been used to 
help characterize the development of the lesion in acrylamide-
induced peripheral neuropathy.  Fullerton & Barnes (1966) 
administered repeated doses (20 - 30 and 10 - 14 mg acrylamide/kg 
body weight per day) to rats.  Concomitant with the appearance of 
major clinical symptoms (after 3 weeks on the high dose and 12 
weeks on the low dose), the maximal motor conduction velocity 
(MCV) was reduced significantly by about 20%.  Similar reductions 
in MCV have been reported for cats (29%) and monkeys (24%) by 
Leswing & Ribelin (1969) and dogs (11%) by Satchell et al. (1982) 
with various dosage regimens and durations of exposure.  The 
reduction in MCV has been correlated with selective degeneration 
of the fast-conducting, large-diameter fibres (Fullerton & 
Barnes, 1966; Hopkins & Gilliatt, 1971; Spencer & Schaumburg, 

    Hopkins & Gilliatt (1971) carried out serial conduction 
studies on motor and sensory nerves in baboons, given relatively 
large total amounts of acrylamide (10 or 15 mg per day for 
several months).  Conduction velocity became reduced in all 
nerves, the greatest reduction being 38% in the anterior tibial 
nerve.  This occurred when there had already been considerable 
reduction in the amplitude of the evoked muscle action potential.  
The authors also studied recovery of conduction velocity and 
action potential amplitude on cessation of intoxication.  In a 
severely affected baboon treated with 15 mg acrylamide/kg body 
weight per day for 94 days, the amplitude of the nerve action 
potentials was still reduced after 1 year, but, after 2 years, it 
had returned to 80% of normal.  The amplitude of the muscle 
action potentials of less severely affected baboons (receiving 
acrylamide at 10 mg/kg body weight per day for 89 or 115 days) 
returned to normal within 2 - 3 months. 

    Sumner & Asbury (1974) measured conduction velocities in 
single sensory nerve fibres in acrylamide-intoxicated cats. They 
reported that the earliest change was failure of muscle spindle 
(type 1a) and Golgi tendon organ (type 1b) afferent terminals to 
initiate impulses.  An important conclusion of the single fibre 
study was that no reduction in conduction velocity could be 
demonstrated in surviving nerve fibres or in the proximal parts 
of fibres that had degenerated peripherally.  These findings 
confirm the suggestion that reduction in MCV is due to 
degeneration of the largest, most rapidly conducting nerve 
fibres.  Lowndes et al. (1978) studied the changes in the 
responses of primary and secondary endings of muscle spindles 
during the early stages of acrylamide intoxication in the cat.  
They reported that the earliest detectable change was an elevated 
threshold and diminished response of muscle spindle endings, 
which occurred prior to abnormalities in neuromuscular function.  
These findings confirmed previous data that large diameter 
sensory fibres are involved early in the toxicity.  Surviving 
axons did not display any slowing of conduction velocity. 

    Von Burg et al. (1981) determined the conduction velocities 
of sensory and motor nerves, both  in vivo and  in vitro, in 
mice administered acrylamide (300 mg/kg body weight per week, 
ip).  Despite an early decrease in isolated sensory (sural) nerve 
conduction velocity, a significant reduction (13%) was not 
observed until the third week of treatment, when tibial nerve MCV 
was also reduced (20%).  Similarly, significant  in vivo  
differences in conduction velocity were not observed until the 
third week, when the conduction velocities of the sciatic-sural 
and sciatic-tibial nerves were reduced by 24% and 43%, 
respectively, although a reduced velocity of the sciatic-sural 
nerve was first observed after 2 weeks of treatment. 

    Anderson (1981) studied nerve action potentials using 
isolated sural and sciatic nerves from rats given a cumulative 
dose of 100 mg/kg body weight.  A change in the waveform of the 
sural nerve action potential and an increase in the relative 
refractory period were observed as little as 24 h after a single 
dose of 100 mg/kg body weight.  In a further study (Anderson, 
1982), no effects were observed on sciatic nerve action 
potential, amplitude, or velocity 24 h after administration of 
25 - 100 mg/kg body weight, despite a significant increase in the 
duration of the evoked muscle action potential.  The significance 
of these findings in the context of early nerve changes is not 
clear.  Central nervous system effects

    There have been relatively few electrophysiological studies 
on the central nervous system.  Kuperman (1958) found 
electroencephalographic (EEG) abnormalities in acrylamide-treated 
cats prior to the development of ataxia (Table 8).  These studies 
clearly indicated that the primary neural locus was subcortical 
and it was proposed that this locus was the mesencephalic 
tegmentum.  The effects of acrylamide on spinal cord function 
were investigated in the cat by Goldstein & Lowndes (1979).  
Animals receiving 7.5 mg acrylamide/kg body weight per day were 
observed to have a reduced unconditioned spinal monosynaptic 
reflex (MSR), when the cumulative dose reached 75 mg/kg body 
weight, with no observable signs of peripheral neuropathy. 

    Boyes & Cooper (1981) measured the far-field somato-sensory-
evoked potentials (SSEPs) in acrylamide-intoxicated rats in order 
to determine the location of dysfunction in the specific 
somatosensory pathway.  The results indicated that damage may 
have occurred throughout the ascending somato-sensory system 
without damage to cortical areas. 

Table 8.  Dose-effect relationship between EEG change and signs of acrylamide intoxication in catsa
Daily dose  Number of  Number       Days to 25%        Cumulative dose resulting in:                    
(mg/kg      cats       showing 25%  increasec    25% increaseb  Maximum    Ataxiac   First neurolog-
body                   frequency                 (range)        increasec  (mg/kg)   ical deficit
weight)                increaseb                 (mg/kg)        (mg/kg)              (range in mg/kg) 
15          5          4            4.5  2      60 - 75        86  11    95  4    75 - 105
25          9          6            3.3  25     25 - 75        71  11    104  15  50 - 100
40          6          6            2.8  29     40 - 80        80  0     80  0    40 - 80

65          5          4            1.3  7      65             65  0     65  0     65

Total       25         20
a  Adapted from:  Kuperman (1958).
b  Asynchronous high-frequency pattern.
c  Mean  percent SD.
    Short-latency somatosensory evoked potentials (SLSEP) in 
monkeys during acrylamide intoxication were studied by Arezzo et 
al. (1982).  The potential produced by activity at the rostral 
end of the fasiculus gracilis (SLSEP2) was reduced, before 
abnormalities were detected in other central tracts or peripheral 

    Electrophysiological evidence of damage to optic nerve 
components was reported by Vidyasagar (1981).  Alterations in 
visual-evoked potentials (VEPs) in female monkeys (macaque) were 
reported by Merigan et al. (1982) following short-term acrylamide 
exposure.  VEP latencies were prolonged after 20 daily doses (10 
mg/kg body weight per day), well before overt signs of toxicity 

7.1.3.  Morphological effects

    The histopathological effects of acrylamide in peripheral 
nerves were investigated by Fullerton & Barnes (1966).  At doses 
inducing clinical effects in animals (section, primary 
axonal degeneration was observed with secondary demyelination of 
the sciatic, tibial, median, and ulnar nerves (as seen in 
Wallerian degeneration).  Distal nerve segments were more 
severely affected than proximal segments.  Medium- to large-
diameter fibres (8 - 9 m) were more susceptible to degeneration.  
Hopkins & Gilliatt (1971) also reported that the longest and 
largest fibres (10 - 16 m) of both motor and sensory nerves were 
most severely affected in acrylamide-intoxicated baboons (19 
mg/kg body weight per day for 118 days).  No abnormalities were 
reported in the proximal sciatic nerve or spinal cord in animals 
exhibiting severe peripheral axonal (distal) degeneration 
(Fullerton & Barnes, 1966). 

    Ultrastructural changes in the nerves of cats, administered 
3 mg acrylamide/kg body weight per day in the drinking-water (252 - 
294 days), were studied by Schaumburg et al. (1974).  Tissue 
biopsies from hind feet, after completion of the study, showed a 
loss of all types of myelinated fibres in distal nerves.  Only a 
few small and large myelinated nerve fibres were seen in plantar 
nerve twigs and most fibres had completely degenerated (bands of 
Bungner).  Many unmyelinated nerve fibres were present.  Most of 
the muscle fibres were vacuolated and shrunken. 

    In studies by Gipon et al. (1977), significant swelling in 
terminal axons and arborizations in rat muscle were reported at a 
cumulative dose of acrylamide of 550 mg/kg body weight (50 mg/kg, 
every other day).  At this dose, 50 - 60% of large peripheral 
nerve fibres showed signs of degeneration.  No histological 
abnormalities were reported in the spinal cord, but the 
techniques employed may not have been adequate. 

    Axonal degeneration in cats given 10 mg acrylamide/kg body 
weight per day was evident by 49 days and was preceded by massive 
accumulation of neurofilaments and enlarged mitochondria in the 

peripheral nerve fibres, which were evident by 22 days (Prineas, 
1969).  Similar findings were reported in the sciatic nerves of 
adult and suckling rats (4 - 12 injections of acrylamide at 50 
mg/kg body weight, 3 doses per week), when no evidence of 
abnormalities could be seen by light microscopy (Suzuki & Pfaff, 
1973).  Accumulation of neurofilaments and invaginations of the 
axolemna have also been observed under similar conditions in dogs 
(Thomann et al., 1974; Satchell et al., 1982). 

    In a study by Schaumburg et al. (1974), morphological changes 
in the terminals of sensory and motor nerve fibres were examined 
in the paws of cats administered acrylamide intraperitoneally at 
10 mg/kg body weight per day, for 7 - 32 days.  Pacinian 
corpuscle axons in the hind feet were the first terminals to 
display degeneration.  The first change was a loss of filopod 
axonal processes, sometimes accompanied by neurofilamentous 
hyperplasia.  The axolemna disappeared and the axoplasm was 
phagocytosed by inner core cells.  Shortly afterwards, changes 
were seen in juxtaposed Pacinian corpuscles, followed by 
degeneration of primary annulospiral endings of muscle spindles, 
secondary muscle spindle endings, and motor nerve terminals, in 
that order.  All these endings accumulated neurofilaments prior 
to degeneration.  These results not only demonstrated 
ultrastructural changes prior to clinical signs, but also that 
sensory nerve terminals were more sensitive than motor nerve 
terminals.  Unmyelinated fibres in somatic nerves were observed 
to be relatively resistant to the effects of acrylamide. 

    Concurrent with axonal degeneration and secondary myelin 
breakdown, Suzuki & Pfaff (1973) reported the appearance of 
endoneural macrophages and a proliferation of Schwann cells in 
the sciatic nerves of adult rats after 26 injections  of 
acrylamide (50 mg/kg body weight, 3 doses per week).  After 4 
injections, microscopic examination revealed myelin figures in 
Schwann cells and enlarged fibres within the sciatic nerve.  These 
changes became more prominent after 8 injections.  Examination of 
nerves from rats receiving 26 injections revealed numerous axonal 
sprouts growing within the Schwann cells.  Honeycomb-like 
interdigitation of Schwann cell-axon networks was observed prior to 
hind limb weakness in acrylamide-intoxicated rats (Spencer & 
Schaumburg, 1977).  Ultrastructural observations in mice led to the 
suggestion that Schwann cell damage occurred after the onset of 
axonal demyelination (Von Burg et al., 1981). 

    Accumulation of smooth endoplasmic reticulum (SER) and other 
organelles within peripheral and central nervous system neuronal 
axons has been reported following acrylamide exposure (Cavanagh & 
Gysbers, 1981; Chrtien et al., 1981).  Such accumulation in 
tibial nerves was observed several days before the onset of 
axonal degeneration (Cavanagh & Gysbers, 1981).  The same changes 
have, however, been observed in other toxic neuropathies and are 
probably of a non-specific nature. 

    Regenerating fibres have been found in nerves of rats 
administered repeated low doses of acrylamide, as shown by the 
presence of fibres with inappropriately short internodal lengths 
for their diameter (Fullerton & Barnes, 1966).  In long-term 
acrylamide intoxication, regeneration may occur simultaneously 
with continuing degeneration, but the regeneration is severely 
retarded.  Kemplay & Cavanagh (1984) reported a prolonged 
inhibition of spontaneous sprouting from motor end-plates at the 
neuromuscular junction in female rats.  This inhibition was 
apparent 24 h after a single dose (90 mg/kg body weight) and 
lasted for 4 weeks.  Acrylamide also reduced the number and 
length of reactionary terminal sprouts following partial 

    Degeneration in large sympathetic and parasympathetic and, 
therefore, probably sensory-myelinated fibres, demonstrating the 
involvement of the autonomic nervous system in acrylamide 
neuropathy, has been observed (Post & McLeod, 1977a).  Studies in 
cats showed impaired neural control of the mesenteric vascular 
bed of a type indicating damage to post-ganglionic unmyelinated 
fibres (Post & McLeod, 1977b).  Acrylamide has been shown to 
cause megaoesophagus in greyhounds (Satchell & McLeod, 1981) due 
to impairment of mechanoreceptors, the afferent fibres of which 
pass through the vagus nerve (Satchell et al., 1982). 

    Ultrastructural changes in the cell bodies (perikarya) of 
dorsal root ganglia (DRG) in cats that had received a cumulative 
dose of 320 mg acrylamide/kg body weight subcutaneously, at 10 
mg/kg body weight per day, were studied by Prineas (1969).  A 
disturbance in granular endoplasmic reticulum (GER), a breakdown 
in polyribosomes, ribosomal dislocation, and an increase in the 
amount of electron-dense material in the cytoplasm were reported.  
Using light microscopy, Sterman (1982) detected a spectrum of 
perikaryal changes in both large and small neurons of lumbar DRG 
in rats administered a cumulative dose of acrylamide at 350 mg/kg 
body weight (50 mg/kg body weight per day).  These changes 
occurred prior to significant peripheral nerve damage and 
included nuclear eccentricity, peripherally-located Nissl bodies, 
and increased numbers of perineuronal cells.  In a further study, 
Sterman (1983) observed ultrastructural changes between days 5 
and 9 of acrylamide treatment (50 mg/kg body weight per day). 
Quantitative morphometric study revealed significant perikaryal 
modifications after 5 - 6 days of treatment, which had progressed 
by 8 - 9 days.  Qualitatively, altered profiles had nuclear 
eccentricity and capping, marked changes in mitochondrial 
morphology, and modifications of ribosomes and Nissl granules.  
Neurons that appeared normal by light microscopy often displayed 
ultrastructural changes. 

    The results of microscopic examination of the brain and/or 
spinal cord have been reported in acrylamide-intoxicated rats 
(Fullerton & Barnes, 1966), mice (Bradley & Asbury, 1970), cats 
(Kuperman, 1958; McCollister et al., 1964), dogs (Thomann et al., 
1974), and monkeys (McCollister et al., 1964).  No abnormalities 
attributable to acrylamide were reported in these studies.  

Prineas (1969) demonstrated ultrastructural changes in nerve 
fibres and boutons terminaux in the anterior spinal grey matter 
after subcutaneous injection of a cumulative dose of 320 mg 
acrylamide/kg body weight (10 mg/kg per day).  Small myelinated 
fibres frequently contained excessive numbers of neurofilaments 
associated with local fibre swelling.  Similarly, 5 - 15% of the 
boutons terminaux were enlarged and contained large numbers of 
neurofilaments. At the cervical level, in the latter stages of 
intoxication (between 32 and 49 days), there were pronounced 
changes in the gracile nucleus.  Small myelinated fibres 
displayed neurofilamentous hyperplasia, many mitochondria, dense 
body and fine granular material, and unusual tubulo-vesicular 
profiles.  Myelin degeneration and axonal abnormalities were 
rarely observed. 

    A selective and progressive loss of Purkinje cells, in the 
cerebella of rats administered 30 mg acrylamide/kg body weight 
per day, was visible from 5 days onwards (Cavanagh, 1982).  The 
ultrastructural features of Purkinje cell damage in the rat have 
been studied in detail by Cavanagh & Gysbers (1983).  No other 
species has so far been studied for these effects. 

    Information on other CNS pathology in acrylamide neuropathy 
is sparse.  Suzuki & Pfaff (1973) demonstrated degeneration of 
spinal cord white matter and the presence of axonal spheroids in 
the cuneate nuclei in the medulla oblongata of rats (cumulative 
dose of 1300 mg acrylamide/kg body weight), and Prineas (1969) 
reported extensive fibre destruction in the dorsal spino-cerebellar 
tracts in the medulla of cats.  Widespread swelling of terminals 
was noted by Cavanagh (1982) in the gracile and cuneate nucleii 
(10th day onwards), and in lumbar and cervical grey matter and 
superior colliculi (14th day onwards), following ip administration 
of acrylamide (30 mg/kg body weight per day) to rats.  Apart from 
Purkinje cell axons, degeneration was uncommon in the CNS regions 

    In summary, long-term absorption of 10 mg acrylamide/kg body 
weight per day, or more, leads consistently to degeneration of 
the distal regions of long sensory, and, later, motor peripheral 
nerve fibres and, also, to a lesser degree, to degeneration of 
the distal regions of long axons in spinal cord tracts.  These 
changes are preceded by accumulation of neurofilaments in the 
distal regions of many axons of the peripheral nervous system 
(PNS) and in the boutons terminaux in the CNS.  Degeneration of 
Purkinje cells of the cerebellum may occur early in intoxication 
with large doses.  Subsequently, degenerative changes also occur 
in autonomic nerve fibres. 

7.1.4.  Biochemical effects

    The primary biochemical interaction responsible for the 
pathogenesis of acrylamide-induced neuropathy is not known. 
However, the effects of acrylamide on various neuronal metabolic 
processes have been the subject of considerable investigation in 
attempts to elucidate the mechanism of toxicity.  These effects 
are discussed in detail in the following sections.  Effects on axonal transport

    Pleasure et al. (1969) injected cats with 3H-leucine and
compared the flow rates of radiolabelled proteins along axons of 
motor and sensory neurons.  An absence of slow axonal transport 
was reported in most acrylamide-treated animals.  This was 
considered to be due to inhibition of protein synthesis or to a 
slight defect in the transport mechanism.  It is suggested that 
acrylamide interferes with "slow" axonal transport and, that such 
an abnormality might result in the observed distal axonal 

    In a subsequent study, Bradley & Williams (1973) injected
3H-L-leucine into the seventh lumbar dorsal root ganglion.
Contrary to the findings of Pleasure et al. (1969), no change was 
found in slow axonal transport (1 - 5 mm/day) in acrylamide-
treated cats; however, there was a decrease in the velocity of 
"fast" axonal transport (100 - 500 mm/day).  Griffin et al. (1977) 
observed a smaller proportion of transported radioactivity (from 
3H-leucine) beyond a nerve crush (sensory and motor) in acrylamide-
treated rats.  Electromicroscopic autoradiography studies indicated 
that this difference might reflect changes in membrane permeability 
followed by impaired sprouting of acrylamide-regenerating nerves 
rather than an abnormality in fast axonal transport.  This 
particular abnormality of regenerative capacity has not been seen 
with other neurotoxic agents, so far examined. 

    Inhibition of "anterograde" transport of acetylcholinesterase 
(AChE) (EC was demonstrated by Rasool & Bradley (1978) 
and Couraud et al. (1982) in ligated sciatic nerves of 
acrylamide-intoxicated rats.  A marked decrease in the 3H-
colchicine binding (75%) capacity in sciatic nerves (distal 
segments) was also reported in these animals (colchicine 
interferes with protein transport in peripheral nerves by binding 
with tubulin, the major protein component of neurotubules) (James 
et al., 1970).  As only 5% of nerve fibres underwent 
degeneration, a decrease in colchicine binding could not be 
attributed to a loss of neurotubular protein during axonal 
degeneration.  It was concluded that the decrease in the axonal 
transport rate of AChE in acrylamide-treated rat sciatic nerves 
was probably the result of changes in the biophysical 
characteristics of the microtubules. 

    Souyri et al. (1981) studied the transport of proteins in the 
ciliary ganglia of acrylamide-treated chickens after an 
intracerebral injection of 3H-lysine.  Multifocal retention of 
labelled proteins occurred in certain preganglionic axons, 
reflecting a local stasis of fast proteins transported in the 
axonal periphery.  In a follow-up study, Chrtien et al. (1981) 
demonstrated that the sites of abnormal retention of fast 
proteins in the ciliary ganglia of chickens were associated with 
multifocal lesions of smooth endoplasmic reticulum (SER), 
characterized by a complex network of tubules intermingled with 

vesicles and mitochondria.  It was reported by Couraud et al. 
(1982) that a 5-fold increase in the A12 form of AChE in the 
sciatic nerves of acrylamide-treated chickens was associated with 
focal disorganizations of SER.  These changes in axonal 
concentrations were found to coincide with a 60% reduction in A12 
AChE anterograde transport.  This observation was in agreement 
with previous reports of impaired fast anterograde axonal 
transport of AChE in the rat (Rasool & Bradley, 1978).  Further 
evidence in support of impaired fast anterograde axonal transport 
in chickens was obtained from the normal mobilities of the G1 and 
G2 molecular forms of AChE that are transported via the slow 
axonal transport system (Couraud et al., 1982).  In contrast, the 
retrograde transport of all AChE forms in chickens was normal. 

    In a study on rats administered acute doses of acrylamide, no 
anterograde transport abnormalities were observed in sciatic 
sensory fibres (Sidenius & Jakobsen, 1983).  However, in a 
similar study by Jakobsen & Sidenius (1983), retrograde build-up 
of protein label was significantly reduced after an acute dose of 
100 mg/kg body weight.  Not only was this abnormality observed 
before neurological signs of neuropathy (motor incoordination) 
had appeared, but it had improved by the time these signs 
disappeared.  Furthermore, the severity of retrograde transport 
abnormalities was related to the degree of neurological 
disturbance.  The retrograde transport of horseradish peroxidase 
(HRP) in rat trigeminal motor neurons was inhibited after a 
cumulative dose of 150 mg acrylamide (30 mg/kg body weight per 
day) (Kemplay & Cavanagh, 1983).  The relationship between 
altered retrograde transport and acrylamide neurotoxicity was 
recently studied in rats (Miller et al., 1983) using labelled 
iodinated nerve growth factor 125I-NGF).  They reported that a 
significant inhibition in retrograde transport that appeared at 
75 mg/kg body weight was correlated with the cumulative dose and 
preceded detectable peripheral nerve dysfunction (seen at 225 
mg/kg).  It was suggested that a reduction in retrograde 
axoplasmic transport might reflect the primary biochemical event 
in acrylamide-induced neuropathy.  Effects on energy production and neuronal metabolism

    The effects of acrylamide on various pathways in intermediary 
metabolism have been extensively investigated.  Hashimoto & 
Aldridge (1970) investigated the effects of acrylamide on  in 
 vitro and  in vivo mitochondrial respiration.  It was concluded that 
oxidative phosphorylation was unaffected, as no effects were 
observed on oxygen uptake and on the ratios of pyruvic and lactic 
acid concentrations in brain cortex slices. 

    Acrylamide might affect pyridine nucleotide (NADP) metabolism 
or function (Kaplan et al., 1973), which could account for the 
greater sensitivity of cats to acrylamide compared with other 
mammals (cats are unable to convert tryptophan to nicotinamide).  
Johnson & Murphy (1977) found that rats administered a cumulative 
dose of acrylamide of 668 mg/kg body weight had elevated levels 
of NAD+ in the cerebral cortex, but there was little evidence of 

interference with pyridine nucleotide function.  In a study by 
Sharma & Obersteiner (1977a), the acrylamide-induced inhibition 
of nerve growth and neuroglia cell growth in chicken embryo 
cultures was attenuated by the addition of nicotinamide, NAD, 
NADP, and glutathione.  More recently, Loeb & Anderson (1981) 
found that supplementing the diet with vitamin B6 (which consists 
of substituted pyridines) delayed the onset and severity of 
acrylamide toxicity in rats. 

    Acrylamide may affect axonal function by interfering with 
glycolysis (Spencer et al., 1979).  Howland et al. (1980) and 
Sabri & Spencer (1980) reported that acrylamide inhibited 
glyceraldehyde-3-phosphate dehydrogenase (GAPDH) (EC, 
phosphofructokinase (PFK), and neuron-specific enolase (NSE) (EC activities  in vitro.  Lactate dehydrogenase (LDH) (EC (an enzyme not directly involved in energy production) 
was not affected.  The association of acrylamide neuropathy with 
inhibition of glycolysis is supported by the results of a study 
by the same group (Dairman et al., 1981), in which the diet of 
acrylamide-exposed rats was supplemented with pyruvate (a key 
molecule in glycolysis).  The authors reported that treated rats 
were protected from the neurotoxic effects of acrylamide.  
However, results of a similar study by Sterman et al. (1983a) 
failed to show a protective effect on acrylamide-intoxicated rats 
despite a 2-fold increase in the dose of pyruvate.  Howland 
(1981) studied the effects of acrylamide on the activities of 
neuron-specific enolase, glyceraldehyde-3-phosphate, and 
phosphofructokinase in the peripheral nerve (sciatic), spinal 
cord, brain, and skeletal muscle of acrylamide-treated cats 
(acrylamide administered at 15 mg/kg body weight per day or 30 
mg/kg per day, sc, for 10 days).  Phosphofructokinase activity 
was not affected in any of the tissues studied.  A decrease in 
the activity of both neuron-specific enolase and glyceraldehyde-
3-phosphate was found in both the CNS and the PNS.  In proximal 
peripheral nerve, only glyceraldehyde-3-phosphate activity was 
reduced. However, in the distal segment, where both neuron-
specific enolase and glyceraldehyde-3-phosphate activities were 
diminished, the former showing a greater decrease (60%) than the 
latter (25%), at both doses of acrylamide.  A decrease in the 
activity of enolase isoenzymes was found to be specific to 
neurons, whereas glyceraldehyde-3-phosphate was also 
significantly reduced in skeletal muscle.  From these results, 
Howland (1981) suggested that the inhibition of neuron-specific 
enolase might account for the tissue specificity of acrylamide 

    The effect of acrylamide on perikaryal protein metabolism has 
been extensively investigated.  Hashimoto & Ando (1973) observed 
a decrease in the  in vitro incorporation of [14C] lysine into 
the sciatic nerve of acrylamide-treated (500 mg/kg diet) rats 
before the onset of neurological symptoms.  After 4 weeks, when 
neurological signs developed, an increase in radiolabel was seen 
in the spinal cord, which was interpreted as an increase in 
protein metabolism because of repair processes.  In studies by 

Kemplay & Cavanagh (1983), a more rapid removal of horseradish 
peroxidase (HRP) from motor neurons was observed in acrylamide-
treated rats compared with controls, suggesting that the 
perikaryon is more catabolically active as a consequence of 
acrylamide intoxication.  A 60% reduction in radiolabel was found 
in the anterior horn cells (AHCs) of the lumbar spinal cord of 
mice given acrylamide at 250 mg/litre in the drinking-water, 7 
days after ip administration of [3H] leucine (Asbury et al., 
1973).  Clinical signs of neuropathy appeared between 14 and 21 
days after treatment.  Ultrastructurally, no alterations were 
seen in the AHCs.  In a later study, Schotman et al. (1977) 
measured the  in vivo incorporation of [3H] leucine into proteins 
of the spinal cord, brain stem, and heart of acrylamide-treated 
rats.  The incorporation of radioactivity into the spinal cord 
and brain stem decreased at a time when animals displayed 
clinical signs of neuropathy.  Increased incorporation of 
radiolabel was observed following cessation of exposure.  A 
similar depression was also observed in heart muscle.  In the 
recovery period, however, labelling of heart proteins was normal.  
No changes were observed in the incorporation of [3H] leucine 
into proteins  in vitro. 

    The above observations indicate a relationship between 
changes in protein metabolism and acrylamide-induced neuropathy.  Effects on CNS neurochemistry

    Dixit et al. (1981c) investigated the effects of acrylamide 
exposure (25 mg/kg body weight, per day, orally, for 21 days) on 
the metabolic disposition of neurotransmitters in the rat brain.  
A significant reduction was reported in the levels of dopamine 
(DA), noradrenaline (NA), and 5-hydroxytryptamine (5-HT) in whole 
brain, at days 14 and 21 of treatment (chronic convulsions and 
mild ataxia were apparent after 14 days of treatment).  The 
distribution of these neurotransmitters in selected regions of 
the brain was also found to be significantly different from that 
in the controls.  Increased monoamine oxidase (EC 
activity (involved in the breakdown of catecholamines) was also 
detected at all stages of treatment.  However, this increase was 
not considered to be directly attributable to the observed 
decrease in neurotransmitters.  Farr et al. (1981) reported a 
dose-dependent increase in the whole brain concentration of 
5-hydroxyindoleacetic acid (5-HIAA) in rats administered acrylamide 
at 5, 15, or 50 mg/kg body weight, per day, for 5 days.  Since 
neither the level nor turnover rate of 5-HT were affected, it was 
suggested that acrylamide interfered with the normal efflux of 
5-HIAA from the brain.  Using the same dosing regime, Aldous et al. 
(1981) found that acrylamide caused a significant increase in the 
levels of dihydroxyphenylacetic acid (DOPAC) in the brains of rats 
in the 5 and 50 mg/kg body weight per day groups.  As there was no 
effect on the rate of DA turnover, the authors concluded that 
acrylamide had an inhibitory effect on the normal efflux of DOPAC 
from the brain.  In a recent report, Fatehyab Ali et al. (1983) 
determined the levels of DA and 5-HT and their acid 

metabolites in several brain regions of the rat.  Both single (50 
or 100 mg/kg body weight) and repeated (10 mg/kg body weight per 
day for 10 days) doses of acrylamide resulted in elevated levels 
of 5-HIAA in all regions studied.  The level of 5-HT was also 
significantly elevated in the frontal cortex and brain stem.  
These responses were dose-dependent.  Turnover studies, following 
inhibition of monoamine oxidase (EC (with pargyline), 
indicated that elevated 5-HIAA levels occurred because of an 
increased rate of 5-HT catabolism.  The only changes in DA and 
DOPAC levels were found in the frontal cortex after repeated 
administration (10 days) of acrylamide. 

    Changes in neuropeptide levels were also observed (Fatehyab 
Ali et al., 1983) 24 h after a single injection of acrylamide (50 
or 100 mg/kg body weight).  At the higher dose, elevated levels 
of beta-endorphin and sustance P were detected in the hypothalamus, 
whereas neurotensin was decreased in the striatum, only at the 
lower dose. 

    Recent studies have focused attention on the effects of 
acrylamide on receptor binding in the CNS.  Agrawal et al. 
(1981b) first reported that rats receiving acrylamide at 25 - 100 
mg/kg body weight, orally, had elevated [3H] spiroperidol binding 
in the striatum, 24 h after dosing.  No significant changes were 
observed in striatal DA levels.  Results showed that acrylamide 
increased both the affinity for spiroperidol and the number of DA 
receptor sites.  In a similar study by Uphouse & Russell (1981), 
rapid changes were detected in [3H] spiroperidol binding and 5-HT 
binding 30 min and 2 h, respectively, after acrylamide treatment 
(100 mg/kg body weight).  For spiroperidol binding, 2 peaks were 
observed during the 24-h period following dosing. 

    When acrylamide was administered prenatally to rats, a 
reduction in striatal dopamine binding sites occurred in the 
offspring, the opposite effect to that seen in adults (Agrawal & 
Squibb, 1981a).  A return to normal values in spiroperidol 
binding was observed within the first 3 weeks after birth. 
Similarly, effects in adults were also reversible; normal values 
were restored within 8 days of cessation of dosing (Agrawal et 
al., 1981a; Uphouse & Russell, 1981).  In a subsequent study 
(Agrawal et al., 1981b), attempts were made to determine the 
specificity of receptor binding changes following a single oral 
dose of 25 - 100 mg acrylamide/kg body weight.  A significant 
increase in the level of striatal [3H] spiroperidol binding was 
observed in rats exposed to 25 or 50 mg/kg body weight.  
Significant increases in glycine in the medulla and 5-HT in the 
frontal cortex were observed after 100 mg/kg body weight.  No 
changes were seen in muscarinic binding in the striatum, 
benzodiazepine binding in the frontal cortex, or qamma-
aminobutyric acid binding in the cerebellum.  Hong et al. (1982) 
showed that acrylamide could affect the postsynaptic DA receptor.  
Postsynaptic receptors in rats were destroyed by the injection 
into the striatum (unilaterally) of kainic acid.  When animals 
were injected with acrylamide (cumulative 200 mg/kg body weight 
over 14 days), significant increases in [3H] spiroperidol binding 

were observed in uninjected striata only.  A parallel acrylamide 
treatment of uninjected animals did not have any significant 
effects on striatal levels of dihydroxyphenylacetic acid and 
homovanillic acid, suggesting that presynaptic events were 
unaffected.  The results of studies on the effects of acrylamide 
on apomorphine-induced stereotypes (Agrawal et al., 1981a; Bondy 
et al., 1981; Tilson & Squibb, 1982) also suggest a postsynaptic 
location of altered DA receptors. 

    In an attempt to determine the functional significance of 
changes in DA receptor binding, the effects of psychoactive 
compounds on motor activity were investigated in acrylamide-
treated rats.  Apomorphine-induced motility was significantly 
attenuated, 24 h after a single dose of 100 mg/kg body weight 
(Agrawal et al., 1981a) and after doses of 10 mg/kg per day for 
10 days (Bondy et al., 1981), indicating a change in the 
sensitivity of the DA receptor.  Similarly, Rafales et al. (1982) 
observed an increased locomotor activity due to a single alpha-
amphetamine challenge in acrylamide-pretreated rats. This 
increased sensitivity persisted at least 5 - 6 weeks beyond 
cessation of acrylamide treatment.  Pretreatment of rats with 
acrylamide at 12.5 mg/kg body weight did not have any significant 
effect on the behavioural suppressant effects of clonidine 
(alpha-adrenergic agonist) and chlordiazepoxide (administered 
24 h after acrylamide treatment), but enhanced the effects of 
apomorphine and alpha-amphetamine (dopaminergic agonists) (Tilson & 
Squibb, 1982).  These data support previous work indicating that 
acrylamide increases the affinity and density of striatal DA 

    The effects of prior handling on acrylamide-induced 
alterations in the striatal DA receptor were investigated by 
Uphouse (1981).  Rats were either handled or were left 
undisturbed for one week prior to oral administration of 100 mg 
acrylamide/kg body weight.  A reduction in [3H] spiroperiodol 
binding was seen, 24 h after exposure to acrylamide, in rats that 
had been gentled.  However, in "non-handled" animals, significant 
effects of acrylamide were not seen.  In a further study, Uphouse 
et al. (1982) found that serum prolactin levels were 
significantly reduced and corticosterone levels, significantly 
increased, in acrylamide-exposed (100 mg/kg body weight) "non-
handled" animals. 

7.2.   In Vitro Toxicity Studies

    The use of  in vitro tests in the screening of acrylamide
for mutagenic effects is described in section 7.4.1.  There
have been a small number of studies on the toxicity of
acrylamide in isolated cell systems.  Hooisma et al. (1980)
investigated the neurotoxic and cytotoxic effects of various
concentrations of acrylamide on several cell culture systems
(chick spinal ganglia, chick muscle cells plus spinal cord
explant, C1300 neuroblastoma cells, Chinese hamster ovary
(CHO) cells, and new-born rat cerebral cells).  Results
indicated that the new-born rat cerebral cell culture was the

most sensitive assay, exhibiting a dose-related and
statistically-significant reduction in the number of neurons
with neurites, after a 16-h exposure to acrylamide solutions
of 7.1 g/litre and 710 g/litre.  Of the other cell types
investigated, only the neurons of chick spinal ganglia were
affected, and then only at a high concentration (7.1 mg/litre).

    Sharma & Obersteiner (1977a) also used chick spinal ganglia 
(dorsal root) to investigate the short-term neurotoxicity of 
acrylamide.  Morphological alteration of nerve fibres and 
neuroglia provided the criteria for the quantification of 
effects.  The concentrations of acrylamide producing half-maximal 
effects for nerve fibres and neuroglia were 15 mg/litre and 27 
mg/litre, respectively; these concentrations are in agreement 
with those reported by Hooisma et al. (1980).  The addition of 
NAD, NADP, nicotinamide, and glutathione (10-4 M) protected 
against the cytotoxic effects of acrylamide (7.1 mg/litre) to 
different extents (Sharma & Oberstemer, 1977a).  Ericsson & Walum 
(1984) reported that acrylamide at concentrations of 35 - 350 
mg/litre elicited dose-dependent cytotoxic effects in cultures of 
rat glioma or mouse neuroblastoma cells.  The addition of 
phenobarbital-induced chick hepatocytes increased the toxicity of 
the highest concentration of acrylamide (350 mg/litre) for both 
cell types, but only significantly for neuroblastoma cells. 

    The use of  in vitro studies in the investigation of the 
effects of acrylamide on neuronal biochemistry has already been 
described (section 7.1.3). 

7.3.  Effects on Other Organs

    A few reports on non-neurological effects have been reported 
following both acute and long-term acrylamide administration. 

    Congestion of the lungs and kidneys was reported by 
McCollister et al. (1964), after adminstration of a lethal dose 
(200 mg/kg body weight) of acrylamide to a monkey.  Microscopic 
examination of the kidneys revealed degeneration of the 
convoluted tubular epithelium and glomerular degeneration with 
albuminous material in the capsular space.  Examination of the 
liver revealed congestion of the sinusoids with fatty 
degeneration and necrosis. 

    An accumulation of porphyrins in the liver was reported by 
Edwards et al. (1978), 5 h after subcutaneous administration of 
acrylamide at 1.5 mmol/kg body weight (107 mg/kg) to rats (Porton 
strain).  An increase in serum aspartate aminotransferase (EC and leucine aminopeptidase (EC was found in 
rats after long-term administration of 5 mg acrylamide/kg body 
weight, per day, indicating an impairment of liver function.  An 
increase in blood thiol levels in rats followed a single dermal 
application of acrylamide at 320 mg/kg body weight (Novikova, 

    Another report (Hashimoto & Aldridge, 1970) showed a rapid 
fall and a gradual return of non-protein sulfhydryl content in 
liver as well as in brain and spinal cord, after a single oral 
dose of acrylamide in rats. 

    Sterman et al. (1983b) found that administration of 50 mg 
acrylamide/kg body weight, per day, to rats caused a significant 
increase in heart rate and systolic arterial blood pressure, 
apparent after the first dose, and progressing throughout the 
exposure period.  Although the exact morphological correlates of 
this dysfunction are not known, these findings expand the work of 
Post & McLeod (1977a,b) (section 7.1.3), which demonstrated an 
involvement of the autonomic nervous system in acrylamide-induced 

    Degeneration of seminiferous tubules has been reported after 
short-term administration of acrylamide to mice (Hashimoto & 
Tanii, 1981) and rats (McCollister et al., 1964).  Huang et al. 
(1982) reported atrophy of the epididymal fat pad, accompanied by 
a severe triglyceride depletion and an increase in tissue 
phospholipids and cholesterol, following ip injection of 
acrylamide in rats at 50 mg/kg body weight, per day, for 10 days. 

    Animal studies have shown that acrylamide is an eye and skin 
irritant.  When acrylamide (concentration not reported) was 
applied to the crown of rabbits' heads, dermatitis, scab 
formation, burns, and ulceration occurred (Hashimoto, 1980). 
Reddening of the skin was observed in rabbits treated with dermal 
applications of 500 mg acrylamide/kg body weight (12.5% solution) 
(McCollister et al., 1964).  The effects of eye contact with 
aqueous solutions containing acrylamide levels of 100 - 400 
g/litre were also studied by McCollister et al. (1964).  The 
application of a 10 g/litre solution produced discomfort and mild 
conjunctival irritation (recovery was complete within 24 h).  The 
application of a 40 g/litre solution caused signs of moderate 
pain, slight conjunctival irritation, and corneal injury (corneal 
healing complete within 24 h). 

7.4.  Genotoxic Effects and Carcinogenicity Studies

7.4.1.  Mutagenicity and other related short-term tests

    Incorporation of low levels of acrylamide into RNA and DNA, 
isolated from the liver and brain of rats 24 h after iv 
administration of 100 mg [1-14C]-acrylamide/kg body weight, was 
demonstrated by Hashimoto & Aldridge (1970): some of the 
radiolabel was available to the carbon pool. 

    Acrylamide (purity unspecified) inhibited transfection of 
colitis bacteriophage DNA in  Escherichia coli CR 63 cells 
(Vasavada & Padayatty, 1981) and resulted in a weak induction of 
the amplification of SV40 DNA inserts in Chinese hamster CO60 
cells, suggesting that acrylamide may produce DNA damage. 

    Acrylamide (purity > 99%) was not mutagenic in  Salmonella 
 typhimurium TA 1535, TA 1537, TA 98, and TA 100, with and 
without metabolic activation systems, in both plate and liquid 
suspension assays (Bull et al., 1984).  Similar results were 
reported by Lijinski & Andrews (1980).  Mukhtar et al. (1981) 
found acrylamide to be non-mutagenic in  S. typhimurium TA 100.  
Negative results in Ames standard tester strains were also 
reported (US EPA, 1982a). 

    American Cyanamid (US EPA, 1982a) reported that acrylamide 
did not induce sister-chromatid exchanges (SCEs) in Chinese 
hamster ovary cells and was inactive in an  in vivo micronucleus 
test on mice.  No details of dosing were given. 

    An increase was found in the frequency of chromosome 
aberrations in the primary spermatocytes of mice treated with 
100, 150, or 250 mg acrylamide/kg body weight (purity 
unspecified) administered intraperitoneally and in mice 
administered a diet containing 500 mg acrylamide/kg for 3 weeks 
(Shiraishi, 1978).  The frequency of chromosomal aberrations was 
not increased in bone marrow cells. 

    Acrylamide was reported to induce cell transformation in 
mouse Balb 3T3 cells in the presence of a metabolic activation 
system and in BHK 21 cells (US EPA, 1982a). 

    It should be noted that acrylonitrile, which is genotoxic in 
a number of test systems, can occur as an impurity in acrylamide 
at concentrations ranging from 1 - 100 mg/kg. 

7.4.2.  Carcinogenicity studies

    Acrylamide (purity > 99%) was tested as an initiator for
skin tumours in groups of 40 female Senar mice.  Doses of
12.5, 25, and 50 mg/kg body weight were given 6 times, over a
period of 2 weeks, by gavage, ip injection, or dermal
application.  Two weeks later, 1 g TPA/animal was applied to
the skin in acetone, 3 times weekly, for 20 weeks.  All
surviving animals were killed at 52 weeks.  Controls received
acrylamide followed by no treatment, or water followed by
TPA.  A dose-related increase in skin tumours occurred with
each route of administration.  In the same study, groups of 16
male and 16 female A/J mice were administered 1, 3, 10, and
30 mg acrylamide/kg body weight by ip injection, 3 times per
week, for 8 weeks.  All animals were killed at 9 months of
age.  Dose-related increases in the number of mice with lung
tumours and the number of lung tumours per mouse were
observed.  The number of lung tumours per mouse were 0.31 and
0.5 in male and female controls and 1.87 and 2.53 in males and
females receiving the high dose.  Similar results were
obtained with oral doses of 6.25, 12.5, and 25 mg/kg body
weight given to groups of 40 male and 40 female A/J mice 3
times per week, for 8 weeks, and killed at 9 months of age
(Bull et al., 1984).

    Groups of 90 male and 90 female Fischer 344 rats, 5 - 6 weeks 
of age, were administered acrylamide (containing less than 1 - 10 
mg acrylonitrile/kg) at 0, 0.01, 0.1, 0.5, or 2 mg/kg body weight 
per day in the drinking-water for 2 years.  Groups of 10 males 
and 10 females were killed at 6, 12, and 18 months.  According to 
a draft final report (Johnson et al., 1984), increased incidences 
of pheochromocytomas, mesotheliomas of the testes, and adenomas 
of the thyroid were observed in males.  At the 0, 0.01, 0.1, 0.5, 
and 2 mg/kg body weight doses, the number of animals with 
pheochromocytomas were 3, 7, 7, 5, and 10, respectively; with 
mesotheliomas of the testes, 3, 0, 7, 11, and 10, respectively; 
and with adenomas of the thyroid, 1, 0, 2, 1, and 7, 
respectively.  The increased incidences of phenochromocytomas at 
the highest dose, mesotheliomas at the 2 highest doses, and 
follicular adenomas at the highest dose were statistically 

    In female rats, increased incidences of pituitary adenomas, 
thyroid follicular tumours, mammary adenomas, adenocarcinomas, 
and oral cavity papillomas were observed.  At the 0, 0.01, 0.1, 
0.5, and 2 mg/kg body weight dose levels, the number of rats with 
pituitary adenomas were 25, 32, 27, and 32, respectively; with 
thyroid follicular tumours, 1, 0, 1, 1, and 5, respectively; with 
mammary adenomas, 10, 11, 9, 19, and 23, respectively; with 
adenocarcinomas, 2, 1, 1, 2, and 6, respectively; and with oral 
cavity papillomas, 0, 3, 2, 1, and 5, respectively.  The 
increased incidences of these tumours at the highest dose level 
were statistically significant compared with controls, and the 
incidence of mammary adenocarcinomas in female rats was 
significantly higher than the incidence in controls, when tested 
by a trend test. 

7.5.  Teratogenicity and Reproductive Studies

    In a 90-day fetal toxicity study of acrylamide in Sprague-
Dawley rats, female rats received 25 or 50 mg acrylamide/kg diet, 
for 2 weeks prior to mating and for 19 days during gestation (US 
EPA, 1980b).  Evaluation of mortality rate, body weight, food 
consumption, mating and pregnancy indices, litter and offspring 
data, and gross post-mortem observations did not reveal any 
significant differences from controls.  There were some fine 
structural differences in the nerves of a number of treated 
animals, such as scattered fibre degeneration in sciatic nerves 
and in one optic nerve; these were considered to be of doubtful 
relationship to any acrylamide effect.  The brain was 
microscopically normal, with no abnormalities in the arrangement 
of cellular components or in the degree of cytological 
development.  There was no evidence of any major teratogenic 

    In another study by Edwards (1976a), acrylamide was 
administered to pregnant Porton rats either as a single iv dose 
(100 mg/kg body weight) on day 9 of gestation or in the diet as a 
cumulative dose of either 200 mg/kg or 400 mg/kg between days 0 
and 20 of gestation.  Apart from a slight decrease in the weight 

of individual fetuses from rats dosed with 400 mg acrylamide/kg, 
no fetal abnormalities were seen, even at doses that induced 
neuropathy in the dams.  No neurological abnormalities were 
observed in weanling rats. The fetal tissue concentration of free 
acrylamide (1.41  0.03 mmol/kg), measured 1 h after iv 
administration to the dams, was very close to that obtained in 
maternal blood (1.28  0.04 mmol/litre), indicating that 
acrylamide crosses the placenta. Ikeda et al. (1983) examined the 
intra-litter distribution of [14C] acrylamide in 4 species of 
animals (rat, rabbit, dog, and miniature pig) with different 
types of placentation.  Acrylamide (as 14C) was present in the 
fetuses of all 4 species at concentrations inversely proportional 
to the number of membrane layers comprising the placenta, i.e., 
fetal concentration in rat > rabbit > dog > pig.  The 
distribution was uniform throughout all litters in each species 
and was independent of fetal sex or uterine position. 

    The effects of acrylamide on the striatal dopamine receptor 
in Fischer 344 rat pups were studied by Agrawal & Squibb (1981).  
An oral dose of 20 mg/kg body weight, administered from day 7 to 
16 of gestation, did not affect the weight or size of litters 
obtained, but did decrease the [3H] spiroperidol (CNS 
catecholamine involved in motor control) binding in the striatal 
membranes of 2-week-old pups (male and female).  The results of 
cross-fostering studies indicated that postnatal (lactational) as 
well as prenatal effects might account for this abnormality.  
Using the same dosing regime, Walden et al. (1981) demonstrated 
that both prenatal and lactational exposure to acrylamide had 
significant effect on the development of certain intestinal 
enzymes (acid phosphatase (EC, alkaline phosphatase 
(EC, beta-glucuronidase, and lactate dehydrogenase (EC in rat pups.  Analysis of milk samples after the 
administration of a single oral dose of 14C-labelled acrylamide 
(100 mg/kg body weight) on day 14 of lactation demonstrated the 
presence of both free and protein-bound compound (Walden & 
Schiller, 1981). 

    No malformations were observed in acrylamide-treated chick 
embryos at dose levels that were clearly associated with 
embryolethality (Kankaanp et al., 1979).  However, similar 
observations were also reported for acrylonitrile, and as this 
compound has been demonstrated to be teratogenic in rats (IARC, 
1979), the significance of these results is not clear. 

    An  in vitro study by Sharma & Obersteiner (1977a) using 
chicken embryo cultures showed a dose-dependent inhibition of 
growth of both nerve and neuroglial cells at concentrations of 
between 0.7 and 700 mg acrylamide/litre.  The addition of 
glutathione, NAD, NADP, and nicotinamide reduced or prevented 

    A marked degeneration of seminiferous tubules was observed by 
McCollister et al. (1964) in male rats, during histological 
assessment, following a short-term feeding study.  Both 
testicular damage with degeneration of the epithelial cells of 

the seminiferous tubules (Hashimoto & Tanii, 1981) and 
spermatocyte chromosome aberrations (Shiraishi, 1978) have been 
reported in mice following acrylamide treatment.  Fatehyab Ali et 
al. (1983) reported that repeated injection of acrylamide (20 mg/kg 
body weight, per day, for 20 days) caused a major depression in the 
plasma levels of testosterone and prolactin in male Fischer-344 

7.6.  Factors Modifying Effects

7.6.1.  Chemical modification of acrylamide toxicity

    Acrylamide-induced neuropathy can be modified by pre- or 
co-administration of various organic compounds. 

    Agrawal et al. (1981a) found that acrylamide-induced changes 
in striatal dopaminergic receptors were completely prevented by 
SKF 525A.  Pretreatment of rats with SKF 525A enhanced 
neurological effects and lethality caused by acrylamide (Kaplan 
et al., 1973) (section 6.1.2). 

    Hashimoto & Tanaii (1981) reported that phenobarbital 
treatment reduced both neuro- and testicular toxicities in 
acrylamide-treated mice.  Pretreatment of rats with either 
phenobarbital or DDT caused a significant delay in the onset of 
ataxia (Kaplan et al., 1973) (section 6.1.2). 

    Concurrent administration of methionine with acrylamide has 
also been shown to reduce the neurotoxic potency of acrylamide 
(Hashimoto & Ando, 1971). 

    Loeb & Anderson (1981) found that supplementing the diet with 
vitamin B6 delayed the onset and severity of acrylamide toxicity 
in rats. 

    It was reported by Dairman et al. (1981) that pretreatment 
with sodium pyruvate partially protected rats from the neurotoxic 
effects of acrylamide based on morphological, biochemical, and 
quantitative behavioural measures.  A similar study by Sterman et 
al. (1983a) failed to show a protective effect despite a 2-fold 
increase in the dose of pyruvate. 

    When  N-hydroxymethylacrylamide was co-administered with 
acrylamide, the time to the onset of acrylamide-related 
neurotoxic effects was reduced (Hashimoto & Aldridge, 1970). 
The toxicity of acrylamide may also be potentiated by the co-
administration of xenobiotics (diethylmaleate cyclohexene oxide) 
which, like acrylamide, is metabolized via glutathione conjugation 
(Refsvik, 1978). 

7.6.2.  Age

    The few studies on the influence of age on acrylamide 
neurotoxicity have produced conflicting results.  Fullerton & 
Barnes (1966) found that rats aged 52 weeks developed 

neurological abnormalities after fewer doses of acrylamide than 
young animals aged 5 weeks.  Similarly, Kaplan & Murphy (1972) 
found that abnormalities of rotarod performance occurred earlier 
in rats aged 11 weeks than in those aged 5 weeks.  Assessment of 
the effects of age on recovery time was not possible because the 
duration of dosing differed at different ages. 

    Dixit et al. (1981b) reported that younger rats exposed to 
acrylamide showed an earlier development of paralysis than older 
rats.  There was also an increased inhibition of hepatic 
glutathione- S-transferase (GST) in young rats.  Maximum 
inhibition of GST was seen on day 15, concurrent with the 
development of hind limb paralysis.  This suggests that the 
enhanced sensitivity of younger animals may be due to reduced 
glutathione (GSH) conjugation with acrylamide, which is a 
detoxification process (section 6.1.2). 

    In studies by Suzuki & Pfaff (1973), suckling rats showed 
signs of neurotoxicity (weight loss and hind limb weakness) after 
5 or 6 injections of 50 mg acrylamide/kg body weight, whereas 
adult rats showed signs after 7 or 8 injections.  The authors 
reported that degenerative changes in the peripheral nerves were 
more severe in suckling rats than in adult rats. 

    Spiroperidol binding was decreased in the striatum of the 
offspring of dams that had been administered acrylamide on days 
7 - 16 of gestation (Agrawal & Squibb, 1981).  The opposite effect 
was seen in adult animals (Agrawal et al., 1981a,b).  As acrylamide 
induces effects on CNS neuro-transmitter functioning, and, as much 
development of the central nervous system occurs post-natally in 
the rat, it might be expected that early post-natal exposure to 
acrylamide would result in permanent CNS damage.  However, there 
have been few studies on this period of development. 

7.6.3.  Sex differences

    There is little information in the literature regarding the 
differences in the responses of male and female animals to 
acrylamide exposure.  An 18-month interim report on the rat, in a 
2-year toxicity-oncogenicity study (US EPA, 1982b), indicated 
that both the incidence of neoplasia and the degree of tibial 
nerve degeneration were significantly increased in male rats 
compared with female rats at a dose level of 2 mg acrylamide/kg 
body weight per day. 

7.6.4.  Species

    No major species differences in response to acrylamide 
exposure have been reported so far, although the cat has an 
increased sensitivity to such exposure.  It has been suggested 
that acrylamide might produce some of its neurotoxic effects by 
affecting pyridine nucleotide metabolism and/or function. The 
dimer of acrylamide resembles nicotinamide, and it has been 
postulated that the synthesis or metabolism of pyridine 
nucleotides in nervous tissue might be inhibited.  This could 

explain the increased sensitivity of the cat, because it cannot 
convert tryptophan to nicotinamide (Kaplan et al., 1973).  
Greyhounds exposed to acrylamide developed peripheral neuropathy 
that was clinically similar to that observed in other species, 
except for the development of megaoesophagus in some exposed 
animals (Satchell & McLeod, 1981; Satchell et al., 1982).  The 
association of megaoesophagus with acrylamide-induced toxicity is 
apparently unique to canines. 

7.7.  Dose-Response and Dose-Effect Relationships

7.7.1.  Dose-response relationships

    Acute LD50 studies have been performed on various mammalian 
species.  McCollister et al. (1964) estimated the LD50 for a 
single oral dose in rats, guinea-pigs, and rabbits to be about 
150 - 180 mg/kg body weight.  The susceptibility of cats and 
monkeys was similar, with iv or ip injections of 100 - 200 mg/kg 
body weight producing severe symptoms or death.  Acute values for 
other mammalian species are shown in Table 9. 

    Acute dose-response data for non-mammalian species are 
scarce.  The LD50 for Japanese quail is 214 (194 - 236) mg/kg 
body weight (Cabe & Colwell, 1981).  Edwards (1975b) found 
considerable variation in the susceptibility of hens to subacute 
doses of acrylamide.  Out of 9 hens treated with acrylamide (50 
mg/kg body weight, orally, 3 times per week), 2 showed ataxia 
after 4 doses, 5 after 6 doses, and 2 after 9 doses.  Similar 
findings were reported in chickens by Souyri et al. (1981). 

    Terminal histopathology in a 2-year toxicity-oncogenicity 
study on acrylamide in Fischer 344 rats revealed a statistically-
significant increase in neoplasms in both male and female animals 
at a dose level of 2.0 mg/kg body weight per day (PTCN, 1983; 
Johnson et al., 1984).  In addition, the incidence of 
mesotheliomas of the scrotal cavity was significantly increased 
in male rats at a dose level of 0.5 mg/kg body weight per day.  
Empirical data from which to construct dose-response 
relationships for effects other than lethality are lacking for 
aquatic organisms (section 9.1.2). 

7.7.2.  Dose-effect relationships

    Although data from which to construct formal dose-effect 
relationships are lacking, a variety of effects have been 
investigated during the development of acrylamide-induced 
neuropathy and, where possible, these will be discussed in 
relation to the minimum doses required to elicit such effects 
and/or to the no-observed-adverse-effect levels.  Manifestations of neuropathy

    The most extensively studied criteria for the assessment of 
acrylamide-induced neuropathy have been the signs of neuropathy 
observed.  A variety of clinical signs resulting from a single 

administration of acrylamide (via different routes) to various 
mammalian species are given Table 6.  Kuperman (1958) reported 
that during repeated administration of acrylamide to cats, signs 
of ataxia (postural and motor incoordination) appeared at 
approximately the same total dose, irrespective of the individual 
dosing schedule (Table 10).  Similarly, a total dose of 500 - 600 
mg/kg body weight, administered in daily (oral) doses of 25, 40, 
or 50 mg/kg, was required to produce ataxia in rats (McCollister 
et al., 1964; Fullerton & Barnes, 1966).  Similar observations 
have been made in dogs (Hamblin, 1956; Thomann et al., 1974) and 
baboons (Hopkins, 1970). 

    This relationship between cumulative dose and the onset of 
clinical signs is less quantitative after long-term 
administration of smaller divided doses.  This is exemplified by 
the data in Table 11.  For example, the cumulative dose of 
acrylamide required to induce initial neuropathic effects (hind-
limb weakness) in rats was 1200 - 1800 mg/kg body weight, after 
daily administration of 6 - 9 mg/kg body weight, in contrast to 
300 - 450 mg/kg, after administration of 20 - 30 mg/kg per day 
(Fullerton & Barnes, 1966). 

    In an attempt to construct a dose-effect relationship in 
rats, Hashimoto (1980) found a better correlation with the 
severity of symptoms using the estimated "steady state" 
concentration of acrylamide in nervous tissue rather than the 
cumulative dose (Table 12).  From this and other data, Hashimoto 
(1980) constructed a graphic relationship between dose, 
administration frequency, the estimated mean concentration of 
acrylamide in nervous tissue, and the severity of ataxia 
following oral administration of acrylamide to rats.  In general, 
a dosing schedule producing a "steady state" nerve concentration 
of between 100 - 300 mol/kg was predicted to produce slight to 
severe ataxia, 300 - 500 mol/kg, severe ataxia, and above 500 
mol/kg, death. 

    In a similar study, Young et al. (1979) demonstrated a 
relationship between the "plateau" concentration of radiolabelled 
acrylamide in the blood and the onset of neuropathy in rats (as 
indicated by a foot-splay test).  The red blood cell 
concentration of radiolabel plateaued at 400 mg acrylamide/kg 
after a total dose of 270 mg acrylamide/kg body weight (30 mg/kg, 
daily, for 9 days), which directly preceded neuropathic 
manifestations.  When acrylamide was administered at 0.05 mg/kg 
body weight per day, the red blood cell concentration rose to a 
level equivalent to 1 mg acrylamide/kg, and no adverse effects 
were observed. 

    Novikova (1979) reported that long-term dermal application of 
acrylamide at 5 mg/kg body weight per day to rats' tails 
(equivalent to 5% body surface area) induced pronounced 
functional neurotoxic effects, characterized by a decrease in 
motor activity, impaired conditioned reflex response, and a 
reduction in body weight (average 31 g).  No consistent adverse 
effects were seen at a dose of 0.5 mg/kg body weight per day. 

Table 9.  Acute LD50 values for acrylamide in mammals
Species   Strain      Sex   Route    LD50  (mg/kg       Survival time   Reference                     
                                     body weight)       (less than)                                  
Mouse     albino      M     oral     170 (130 - 220)a   -               Hamblin (1956)                
Mouse     ddy         M     oral     107 (76 - 151)a    1 week          Hashimoto & Sakamoto (1979)   
Rat       -           -     ip       120                2 days          Druckrey et al. (1953)        
Rat       Porton      F     oral     203 (166 - 249)a   3 days          Fullerton & Barnes (1966)     
Rat       Wistar      -     oral     124                -               Paulet & Vidal (1975)         
Rat       Fisher 344  M     oral     251 (203 - 300)a   1 day           Tilson & Cabe (1979)          
Rat       Fisher 344  M     oral     175 (159 - 191)a   1 week          Tilson & Cabe (1979)          
Rat       -           -     dermalb  400                -               Novikova (1979)               
Guinea-   -           -     oral     170                -               Ghiringhelli (1956)           
Cat       -           -     iv       85                 -               American Cyanamid (1961)      
a  95% confidence intervals.
b  A 4-h application time.
Table 10.  Cumulative dose and time to ataxia in cats given repeated
doses of acrylamide (iv and ip)a
Dose per day      Number of cats      Cumulative dose    Days to
(mg/kg                                (mg/kg body        ataxia
body weight)                          weight SD)     
1                 5                   101  30           125  26
2                 7                   132  24           91  18
5                 3                   78  5             22  3
10                8                   126  29           19  6
15                5                   102  10           9  11
25                11                  102  20           6  2
40                6                   73  21            3  1
50                3                   100  0            2  0

          Total:  48           Mean:  102  6 (SE)
a  Adapted from:  Kuperman (1958).
    In a 12-week study on new-born rabbits, haematological, 
serum, biochemical, gross, and microscopic examinations did not 
reveal any abnormalities in animals administered 0.5 or 5 mg 
acrylamide/kg per day.  However, clinical signs of neuropathy 
were observed in animals administered 50 mg/kg per day (first 
seen on day 24) (Drees et al., 1976). 

    McCollister et al. (1964) reported that doses of 0.3, 0.9, 
and 3 mg acrylamide/kg, administered in the diet to rats (10 
rats/sex per dose, Dow Wistar strain), for 90 days, did not cause 
any adverse effects. 

    An 18-month interim report (US EPA, 1982b) indicated that 
there were no signs of neurological changes in rats (10 rats/sex 
per dose) administered acrylamide at doses of 0.01, 0.1, 0.5, and 
2 mg/kg body weight per day, though a slight, but significant, 
reduction in body weight was seen after 3 months in rats 
administered 2 mg/kg per day.  A statistically-significant 
increase in mortality rate was seen in acrylamide-treated rats 
(male and female) at completion of the study (2 years) (Johnson 
et al., 1985). 

Table 11.  Acrylamide doses producing early clinical signs of peripheral neuropathy in various mammals
Animal   Route of   Dose     Schedule            Days to initial   Total administered  Reference       
         adminis-   (mg/kg                       effect            dose (mg/kg body                   
         tration    body                         (No. of doses)    weight)                        
Rat      oral       100      2 doses per weeka   21(6)b            600                 Fullerton &     
 (adult) oral       100      1 dose per week     42(6)             600                 Barnes (1966)   
         oral       100      1 dose per 2 weeks  210(15)           1500                                
         ip         75       1 dose per day      4.6c              345                 Kaplan & Murphy 

         ip         50       1 dose per day      2(2)d             100                 Gipon et al.    
         ip         50       3 doses per week    18(7-8)           350 - 400           Suzuki & Pfaff  
         oral       40       daya                14                560                 McCollister et  
                                                                                       al. (1964)      
         ip         40       1 dose per day      6.7c              268                 Kaplan et al.   
         oral       30       daya                21                630                 McCollister et  
                                                                                       al. (1964)      
         ip         30       1 dose per day      10.7c             321                 Kaplan et al.   
         oral       30       1 dose per day      12                360                 Loeb & Anderson 
         oral       25       5 doses per week    28(20)            500                 Fullerton &     
                                                                                       Barnes (1966)   
         ip         25       1 dose per day      16.8c             420                 Kaplan & Murphy 
         oral in    20-30f   5 doses per week    21(15)            300 - 450           Fullerton &     
          diet                                                                         Barnes (1966)   

Table 11.  (contd.)
Animal    Route of   Dose    Schedule            Days to initial   Total administered  Reference
          adminis-   (mg/kg                      effect            dose (mg/kg body
          tration    body                        (No. of doses)    weight)
Rat       oral in    15-18f  5 doses per week    28(20)            360 - 630           Fullerton &   
 (contd.)  diet                                                                         Barnes (1966)   

          oral in    10-14f  5 doses per week    84(60)            600 - 840           Fullerton &     
           diet                                                                         Barnes (1966)    
          oral       9       daya                56e               504                 McCollister et   
                                                                                       al. (1964)       
          oral in    6-9f    5 doses per week    280(200)          1200 - 1800         Fullerton &      
           diet                                                                        Barnes (1966)    

Cats      ip         50      1 dose per day      2(2)              100                 Kuperman (1958)

          oral       20      1 dose per day      14 - 21           280 - 420           Leswing &
                                                                                       Ribelin (1969)

          ip         20      1 dose per day      5                 100                 Schaumburg et
                                                                                       al. (1974)

          ip         10      1 dose per day      13 - 16           130 - 160           Schaumburg et
                                                                                       al. (1974)

          oral       10      5 doses per day     26(20)            200                 McCollister et
                                                                                       al. (1964)

          sc         10      1 dose per day      17 - 22           170 - 220           Prineas (1969)

          oral in    3       5 doses per week    68                144                 McCollister et
           food                                                                        al. (1964)

          oral in    3       1 dose per day      70, 163           210, 489            Schaumburg et
           water                                                                       al. (1974)

          ip         1       5-6 doses per week  125               101                 Kuperman (1958)

          iv         1       5 doses per week    180               130                 Hamblin (1956)
Table 11.  (contd.)
Animal    Route of   Dose    Schedule            Days to initial   Total administered  Reference
          adminis-   (mg/kg                      effect            dose (mg/kg body
          tration    body                        (No. of doses)    weight)
Dogs      oral       15      1 dose per day      21b               315                 Thomann et al.

Dogs      oral       10      1 dose per day      28 - 35b          280 - 350           Hamblin (1956)
          oral       7       1 dose per day      44 - 67           340 - 460           Satchell & 
                                                                                       McLeod (1981) 
          oral       5       1 dose per day      21b               105                 Thomann et al.
Mice      oral       54      2 doses per week    14(4)c            216                 Hashimoto &   
                                                                                       Sakamoto (1979)

Rabbits   dermal     200     2 doses per week    1 - 3             400 - 1200          Hashimoto (1980)
          dermal     50      1 dose per day      24                900                 Drees et al.

          sc         40      2-3 doses per week  14 - 21           240                 Inomata (1967)

Primates  oral in    25      1 dose per day      42                630                 Hopkins (1970)

          oral in    20      1 dose per day      16                320                 Hopkins (1970)

          oral in    10      1 dose per day      42 - 97           420 - 970           Hopkins (1970)

          oral in    10      5 doses per week    48(34)            340                 McCollister et
           water                                                                        al. (1964)
Adapted from: Conway et al. (1979).
a  Signs of intoxication based on electrorod measurements.
b  Acrylamide mixed with food; dose estimated by McCollister et al. (1964).
c  Signs of intoxication probably appeared earlier than noted.
d  Signs of neuropathy based on decreased rearing ability.
e  Effect noted in only 1/20 exposed animals.
f  Estimated by authors.

Table 12.  Dose-effect relationships of repeated acrylamide administration to ratsa
Route   Dose     Schedule       Days to     Cumulative     Estimated mean    Signs           Reference  
        (mg/kg                  signs       dose (mg/kg    concentration                                
        body                    (number     body weight)   of acrylamide                                
        weight)                 of doses)                  in nervous                                   
                                                           tissue (mol/kg)                             
Oral    100      2 doses        21 (6)      600            310 - 450         severe para-    Fullerton  
                 per  week                                                   lysis of        & Barnes  
                                                                             hindlimbs       (1966)    
Oral    100      1 dose         56 (8)      800            150 - 300         severe para-    Fullerton 
                 per  week                                                   lysis of        & Barnes  
                                                                             hindlimbs       (1966)    
Oral    100      1 dose every   240 (24)    2400           90 - 240          severe para-    Fullerton 
                 10 days                                                     lysis of        & Barnes  
                                                                             hindlimbs       (1966)    
Oral    100      1 dose         28 (4)      400            140 - 280         moderate        Fullerton 
                 per week                                                    paralysis of    & Barnes  
                                                                             hindlimbs       (1966)    
Oral    100      1 dose every   392 (28)    2800           50 - 200          slight weak-    Fullerton 
                 2 days                                                      ness of         & Barnes  
                                                                             hindlimbs       (1966)    
Oral    50       5 doses        15 (12)     600            410 - 470         severe weak-    Fullerton 
                 per week                                                    ness and        & Barnes  
                                                                             death           (1966)    
Oral    25       5 doses        28 (20)     500            230 - 270         slight weak-    Fullerton 
                 per week                                                    ness of         & Barnes  
                                                                             hindlimbs       (1966)    
Oral    10       5 doses        77 (55)     550            100 - 110         no effects      Fullerton 
                 per week                                                                    & Barnes  
a  Adapted from: Hashimoto (1980).
    In a 1-year feeding study by McCollister et al. (1964), 
acrylamide was administered to cats at concentrations of 0.03, 
0.1, 0.3, 1, 3, or 10 mg/kg diet per day, for 5 days per week (2 
animals per dose level and 2 controls).  Cats administered 10 
mg/kg per day developed definite weakness of the hind limbs after 
26 days.  Both cats exposed to 3 mg/kg per day showed twitching 
motion in the hindquarters after 26 days and signs of hind-limb 
weakness after 68 days.  In a study by Schaumburg et al. (1974), 
2 cats receiving 3 mg acrylamide/kg per day developed a gait 
disorder (after 70 and 163 days, respectively) and hind-foot drop 
and muscle weakness within 7 months.  One cat receiving 1 mg/kg 
per day, for 1 year, showed slight signs of neuropathy as 
diagnosed by twitching (after 26 days) and stretching of the 
hindquarters (after 240 days).  No adverse effects were seen in 
the cat receiving 0.3 mg/kg per day (cumulative dose 78 mg/kg 
body weight), which survived to the end of the study (McCollister 
et al., 1964). 

    The same authors (McCollister et al., 1964) carried out a 
long-term study on female monkeys (daily doses of 0.03, 0.1, 0.3, 
1, 3, or 10 mg acrylamide/kg) (1 animal at each dose level).  The 
monkey receiving 10 mg/kg per day developed weakness of the 
hindquarters after 48 days (cumulative dose 340 mg/kg body 
weight) and severe weakness after 69 days.  No significant 
clinical signs of neuropathy were observed in the monkey 
administered 3 mg/kg per day.  Spencer (1979) reported that 
Rhesus monkeys (number of animals not stated) exposed to 
acrylamide at 0.5, 1, and 2 mg/kg body weight per day, for 546, 
338, 325 days, respectively, did not show any adverse clinical 
effects.  Electrophysiological effects

    No-observed-adverse-effect levels and/or minimum-effect 
levels are not available for any acrylamide-induced 
electrophysiological effects (section 7.1.1).  However, there are 
some quantitative data relating electrophysiological measurements 
with the development of other neurological effects. 

    Goldstein & Lowndes (1979) found that cats administered 
acrylamide at 7.5 mg/kg body weight per day exhibited a reduced 
unconditional spinal monosynaptic reflex (MSR) at a cumulative 
dose of 75 mg/kg body weight, when no clinical signs of 
neuropathy were evident. 

    Electroencephalographic (EEG) abnormalities were found in 
acrylamide-treated cats prior to the development of ataxia 
(Kuperman, 1958).  The dose-effect relationship between EEG 
change and signs of intoxication are shown in Table 8.  Morphological effects

    Fullerton & Barnes (1966) did not find any abnormalities 
(using light microscopy) in the brain and spinal cord tissue of 
neuropathic rats that had been administered acrylamide in 
approximate daily doses of between 6 and 30 mg/kg body weight, 
the total dose ranging from 300 - 1800 mg/kg. 

    Changes in peripheral nerves that were considered significant 
were reported in both the 93-day study of Burek et al. (1980) and 
the 2-year study reported to the US EPA (1980c).  In the former 
study, these changes occurred with a daily intake of 1 mg/kg, 
while in the latter, they occurred more frequently, with an 
intake of 2 mg/kg per day.  However, similar changes were found 
in nerves from the low-dose groups (0.01, 0.05, 0.1, and 0.5 
mg/kg per day), and also in the nerves of the control animals.  
Moreover, the interpretation of these changes, which are not 
necessarily degenerative in nature (e.g., Schwann cell 
invaginations into axons and dense body accummulations), is 
questionable.  This is particularly so in the context of tissue 
changes in the ageing rat. Because of these uncertainties, and 
because of the importance of determining the lowest doses at 
which, with long-term intake, significant morphological changes 
may be found, there is a strong need to confirm these findings. 

    Cavanagh (1982) observed a selective loss of Purkinje cells 
in rats given 30 mg acrylamide/kg body weight per day. The first 
changes were seen on day 3.  The same dose caused inhibition of 
nerve regeneration and spontaneous terminal sprouting induced by 
partial denervation of motor nerves (Kemplay & Cavanagh, 1984). 

    Accumulation of neurofilaments and enlarged mitochondria in 
the peripheral nerve fibres, seen after 22 days in cats (5 
animals per sex) administered 10 mg acrylamide/kg per day, 
preceded axonal degeneration, which was observed after 49 days 
(Prineas, 1969).  Similar findings were reported in rats by 
Suzuki & Pfaff (1973) (section 7.1.2). 

    Schaumburg et al. (1974) observed degeneration of myelinated 
distal nerve fibres in cats (2 animals) administered 3 mg 
acrylamide/kg body weight per day (in the drinking-water) for 252 
and 294 days, respectively.  At terminal necropsy (1 year), 
microscopic examination of cats (1 animal per dose) did not 
reveal any evidence of adverse effects on CNS tissues (brain and 
spinal cord) after administration of 0.3, 1, or 3 mg 
acrylamide/kg per day. Similar findings were reported in monkeys 
administered between 0.03 and 10 mg/kg body weight per day for 
one year (McCollister et al., 1964).  Spencer (1979) reported 
that Rhesus monkeys exposed to 3 mg/kg per day for 49 weeks 
developed minor pathological changes in the CNS.  No adverse 
effects were seen in monkeys exposed to 0.5, 1, and 2 mg 
acrylamide/kg per day for 546, 338, and 325 days, respectively.  Effects on axonal transport

    Miller et al. (1983) reported that administration of single 
doses of acrylamide (25 - 100 mg/kg body weight) to rats 
inhibited the fast axonal retrograde transport of the iodinated 
nerve growth factor [125I-NGF], in a dose-dependent manner.  On 
repeated administration (15 mg/kg body weight per day), 
acrylamide caused significant inhibition in retrograde transport 
at a cumulative dose of 75 mg/kg body weight, which preceded 
clinical detection (using a foot-splay method) of peripheral 
nerve dysfunction, seen at a cumulative dose of 225 mg/kg body 
weight.  Neurobehavioural effects

    Pryor et al. (1983) used a battery of neurobehavioural tests 
to examine the dose- and time-dependent effects of acrylamide.  
Rats were dosed by gavage, 5 days per week, with 0, 6.6, 9.6, 
13.8, or 19.9 mg/kg body weight per day for 15 weeks.  
Neurobehavioural assessment of sensory function (responsiveness 
to a novel auditory and tactile stimulus, reactivity to a noxious 
thermal stimulus, quasi-psychophysical assessment of auditory, 
visual, and pain modalities), motor function (grip strength, 
motor coordination), and conditioned avoidance responding was 
made prior to exposure, and every 3 weeks during dosing.  The 
high dose of acrylamide resulted in some deaths by the 7th week 
of dosing (cumulative dose of about 700 mg/kg).  Lower doses of 
acrylamide (9.6 or 13.8 mg/kg per day) resulted in significant 
dose- and time-dependent decreases in motor function (fore and 
hind limb grip strength, impaired motor coordination).  The onset 
of these effects was independent of alterations in body weight. 
Full or partial recovery of function was observed up to 6 weeks 
after dosing ceased.  Acrylamide had little or no effect on the 
sensory modalities assessed.  Any alterations in sensory function 
or the ability to perform a discriminated avoidance response were 
always associated with impaired motor function.  However, tactile 
or vibration sense modalities were not assessed in these studies.  
The lowest dose of acrylamide (6.6 mg/kg per day) did not induce 
any statistically-reliable effects in any of these screening 
tests.  The determination of no-observed-adverse-effect levels 
for neurobehavioural func-tions, using more sensitive or 
selective (for vibration or tactile sensations) methods, or 
species other than the rat, has still to be carried out. 


8.1.  Clinical Studies and Case Reports

    In man, as in animals, acrylamide causes local irritation on 
contact with the skin, neurological symptoms, and weight loss due 
to systemic effects produced following skin absorption, 
inhalation, and ingestion. 

    A variety of symptoms have been described in cases of 
acrylamide poisoning, suggesting involvement of both the central 
and peripheral nervous systems, as well as the autonomic nervous 
system.  Symptoms include local irritation of the skin or mucous 
membranes, with blistering and desquamation of the skin of the 
hands (palms) and/or feet (soles) (Kesson et al., 1977; Mapp et 
al., 1977), muscular weakness, paraesthesia, numbness in hands, 
feet, lower legs, and lower arms (Garland & Patterson, 1967; Mapp 
et al., 1977), and unsteadiness, with difficulties in walking and 
standing (Takahashi et al., 1971).  Some patients also experience 
unusual fatigue and sleepiness, memory difficulties, and 
dizziness (Takahashi et al., 1971).  Vegetative symptoms such as 
micturition and defaecation difficulties (Garland & Patterson, 
1967), and excessive sweating and reddening of the hands and feet 
(Takahashi et al., 1971; Kesson et al., 1977) can occur. 

    The clinical signs exhibited in cases of poisoning are 
consistent with the reported symptoms.  Thus, contact dermatitis, 
blueness and sometimes redness of feet and hands (Auld & Bedwell, 
1967), loss of peripheral tendon reflexes (ankle and lower arm), 
impairment of vibration sense and loss of other sensation, as 
well as muscular wasting in peripheral parts of the extremities, 
have been observed (Takahashi et al., 1971; Kesson et al., 1977).  
Truncal ataxia, nystagmus, and slurred speech have also been 
observed (Igisu et al., 1975). 

    In severe subacute poisoning, occurring after exposure for 
about one month, Igisu et al. (1975) described confusion, 
disorientation, memory disturbances, and hallucinations.  In 
other cases of poisoning, after high, but less extreme levels of 
exposure, drowsiness and lack of concentration have been 
described.  Truncal ataxia may be prominent.  This may be due 
either to involvement of the cerebellum (Cavanagh & Gysberg, 
1983) or to sensory degeneration.  Peripheral neuropathy develops 
insidiously after the appearance of local dermatitis or central 
nervous system involvement.  Following long-term low-level 
exposure, dermatitis and peripheral neuropathy may be the only 
detectable manifestations (Garland & Patterson, 1967). 

    In most reported cases of poisoning, signs and symptoms 
slowly disappeared after exposure to acrylamide ceased and, 
although improvement sometimes took from months to years, most 
cases finally recovered (Kesson et al., 1977; Mapp et al., 1977).  
However, in more severely affected cases, various combinations of 
residual ataxia, distal weakness, reflex loss, and sensory 

disturbances have been observed for up to at least 15 months 
after cessation of exposure (Garland & Patterson, 1967; 
Fullerton, 1969). 

    Although cerebrospinal fluid cell counts and glucose contents 
remain normal, fluid proteins may be slightly increased; levels 
ranging from 300 to 700 mg/litre have been reported in 3 cases 
(Garland & Patterson, 1967; Igisu et al., 1975). 

    Electrophysiologically, the most consistent finding is a 
reduction in nerve action potential amplitude in distal parts of 
sensory nerves (Fullerton, 1969; Takahashi et al., 1971). In 
contrast to findings in animal studies, changes in maximal motor 
nerve conduction velocity in human beings have been found to be 
minimal (Le Quesne, 1980).  Neuropathy, reported in human cases, 
has been less severe than that in animals, which show a greater 
reduction in conduction velocity. 

8.2.  Epidemiological Studies

    Epidemiological studies relating acrylamide exposure to the 
prevalence of signs of adverse effects or to body burden have not 
been reported in the literature so far.  Because most cases of 
poisoning have occurred through skin absorption, and a suitable 
biological index of body burden is lacking, the dose factor is 
difficult to determine at present. 

8.3.  Dose-Effect and Dose-Response Relationships

    A total of over 60 cases of acrylamide poisoning has been 
reported in the literature (Table 13).  In no case has it been 
possible to reconstruct dose level reliably, and no information 
concerning acrylamide concentrations in body organs or body 
fluids has been reported.  Thus, quantitative human data 
concerning dose-effect and dose-response relationships are not 
available.  However, the clinical reports are consistent with 
observations from animal studies (section 7.1) in that after 
acute exposure to relatively high levels of acrylamide, signs and 
symptoms of toxicity indicate early central nervous system 
involvement, while long-term exposure to low levels is 
characterized by an insidious onset of signs of peripheral 
neuropathy.  In cases of acute exposure, signs of peripheral 
neuropathy generally appear with a latency of several weeks 
following the development of signs of central nervous system 
toxicity.  Thus, Igisu et al. (1975) reported 5 cases of 
acrylamide poisoning due to the ingestion of contaminated well 
water.  It is likely that the exposure was high, as all 5 cases 
had a variety of signs and symptoms of central nervous system 
toxicity.  However, after a few weeks, signs of peripheral 
neuropathy also appeared.  In a report by Hashimoto (1980), the 
estimated cumulative ingestion of acrylamide was calculated to be 
about 200 mg/kg body weight based on an estimated average 
concentration of 800 mg/litre in the drinking-water.  This is the 
only dose-effect relationship reported in human beings.  Similar 
cases with central nervous system symptoms have been reported 

from occupational exposure to acrylamide, where absorption 
occurred mainly through the skin (Mapp et al., 1977).  However, 
in general, acrylamide exposure levels in the occupational 
environment are low and, therefore, most cases of poisoning show 
only signs and symptoms of peripheral nerve dysfunction.  Thus, 
it appears that the central nervous system is the critical organ 
following acute acrylamide poisoning, but that the peripheral 
nervous system is more sensitive to prolonged exposure. 

Table 13.  Cases of acrylamide intoxication in mana
Report  Year   Number of   Occupation           Length of    Reference
               patients                         exposure        
1       1953-  5 - 6       production of        5 months     Kuperman (1957)
         54                acrylamide from                      
2       1961   10          production of        3 months -   Fujita et al. (1960)
                           acrylamide from      1 year          
3       1967   1           production of        5 months     Anon (1967)
4       1967   1           production of        1 month      Garland & Patterson (1967)
               4           production of        2 months -             
                           flocculators         1 year          
               1           production of        4 weeks         
5       1967   1           dissolution of       2 weeks      Auld & Bedwell (1967)
6       1969   6           production of        6 months     Morviller (1969)
7       1970   1           construction work    6 months     Graveleau et al. (1970);
                           for waterproofing                 Cavigneaux & Cabasson (1971)
8       1971   10          production of paper  2 months -   Takahashi et al. (1971)
                           strengtheners        1 year          
9       1971   3           weighing of          10 days      Satoyoshi et al. (1971)
10      1975   5           non-occupational     10 days      Morimoto et al. (1975);
                           exposure                          Mori (1975); Igisu et al.
11      1976   1           mixing of            3 months     Davenport et al. (1976)
12      1977   6           polymerization of    2 weeks      Kesson et al. (1977)      
                           acrylamide in                            
13      1977   5           polymerization of    4 - 12       Mapp et al. (1977)
                           acrylamide in        weeks           
                           road tunnelling                      
a  Adapted from: Hashimoto (1980).

9.1.  Aquatic Organisms

9.1.1.  Invertebrates

    A qualitative survey of aquatic insects in a brook before and 
after exposure to approximately 50 g acrylamide/litre, for 6 h, 
showed a decrease in the population size and diversity of 
species.  Within 3 weeks, only  Hydropsyche instabilis  was 
observed in the river.  When the brook was examined 4 and 8 weeks 
after the final acrylamide addition, recolonization of 
Chironomidae,  Baetis rhodani,  and  Amphinemura sulcicollis  was 
found at low population densities (Brown et al., 1982). 

9.1.2.  Fish and amphibia

    In static exposures of fathead minnows to acrylamide, the 
LC10, LC50, and LC90 values (96-h) were 89, 124, and 173 
mg/litre, respectively (Davis et al., 1976).  Goldfish tolerated 
a continuous 30-day exposure to 50 mg acrylamide/litre water.  
Exposure to 100 mg/litre, however, was lethal in 5 - 7 days 
(Edwards, 1975b).  Bridie et al. (1979b) reported that the LC50 
(96-h) for goldfish was 160 mg/litre, and the LC50 (96-h) for 
fathead minnows was reported to be 124 mg/litre by Davis et al. 
(1976).  Blackhead minnows survived for over 2 weeks in an 
acrylamide concentration of 60 mg/litre, but showed marked 
mortality at a concentration exceeding 1000 mg/litre (Cherry et 
al., 1956).  The LC50 (96-h) for Harlequin fish  (Rasbora 
 heteromorpha)  at 20 C and pH 7 was 130 mg/litre (McKim & 
Anderson, 1976) with a 3-month extrapolated figure of 10 

    Both frogs and goldfish were sensitive to the general toxic 
effects of acrylamide.  Three doses of 50 mg/kg in 1 week killed 
3 out of 5 frogs.  Continuous exposure of goldfish to 100 
mg/litre acrylamide killed all 7 in a group in 5 - 7 days, but no 
effects were seen at 50 mg/litre for up to 30 days.  No adverse 
effects were seen in either species at sublethal doses. 

9.2.  Terrestrial Plants

    No significant effects on either germination, pollen tube 
formation, or growth of  Impatiens sultanii  were found, when 
acrylamide (10 - 2000 mg/kg) was added to the basal medium 
(Bilderback, 1981).  However, Japanese workers have shown 
interference with germination and growth in Chinese cabbage seeds 
when the soil was treated with acrylamide concentrations at 50 
mg/kg and above.  Disturbances in growth were also observed at a 
concentration of 10 mg/kg (Sonoda et al., 1977). 

9.3.  Microorganisms

    No detailed studies on the effects of acrylamide on 
microorganisms have been reported, but there have been a number 

of studies on the degradation of acrylamide by microbes (Croll et 
al., 1974; Lande et al., 1979; Brown et al., 1980a; Arai et al., 

    Cherry et al. (1956) noted that the biota that developed in 
river water treated with 10 mg/litre acrylamide was mixed and 

    Because of the limited amount of data available on the 
effects of acrylamide on the environment and the levels of 
exposure, the Task Group was unable to make a full evaluation. 

    Acrylamide, because of its the high water solubility, has a 
potential for entering ground water and thus drinking-water 
supplies.  However, accumulation in the environment and 
biomagnification in the food chain are not likely (section 4) 
under most circumstances, because of its biodegradation by 


    Numerous applications have been described for the polymers 
and copolymers of acrylamide and its derivatives (MacWilliams, 
1973).  Many analogues and derivatives of acrylamide have been 
studied for neurotoxic potential in an attempt to elucidate 
structure-activity relationships (Table 14).  Barnes (1970) 
investigated the short-term neurological effects of 9 substances, 
related to acrylamide, administered in the diet to adult rats.  
Dose schedules were such that, with acrylamide, acute poisoning 
and neuropathy would have resulted.  Seven of the compounds were 
without effect.  Of these, the most important were acrylonitrile, 
which is present as a residual impurity in commercial acrylamide, 
and methacrylamide and  N,N' -diethylacrylamide, which are used 
commercially.   N -methylacrylamide and  N -hydroxymethylacrylamide 
produced some neurotoxic effects.  Animals poisoned with high 
doses of  N -methylacrylamide showed signs of weakness, while 
those receiving  N -hydroxymethylacrylamide developed fine tremors 
and chronic urinary retention.  The gross clinical picture of 
muscular weakness was not observed with  N -hydroxymethylacrylamide.  
Interpretation of data from this study was, however, clouded by 
the possibility of acrylamide contamination of the test compounds 
(Barnes, 1970). 

    In another study, Hashimoto & Aldridge (1970) measured the 
reactivity of several acrylamide analogues with glutathione (GSH) 
in an attempt to correlate reactivity with toxicity. Acrylonitrile, 
which reportedly has no neurotoxic effects, had a greater 
reactivity with GSH than acrylamide.   N -hydroxymethylacrylamide, 
which has been reported to have minimal neurotoxic effects 
(Barnes, 1970; Edwards, 1975b; Hashimoto et al., 1981), had a 
reactivity with GSH that was similar to that of acrylamide.  The 
authors reported that acutely-administered acrylamide was 
approximately 2.5 times more toxic than  N -hydroxymethyl-
acrylamide.  These results indicate that reactivity with GSH is 
not an important criterion in the assessment of neuropathy.  Rats 
fed acrylamide in the diet showed decreased growth rate and 
ataxia, while rats fed  N -hydroxymethylacrylamide were 
asymptomatic.  However, when co-administered with acrylamide, 
 N -hydroxymethylacrylamide accelerated the onset of neurotoxic 
symptoms (section 7.6.1). Edwards (1975b) described 
 N -hydroxymethylacrylamide,  N,N -diethylacrylamide, and 
 N -methylacrylamide as being neurotoxic for rats. 

Table 14.  Summary of comparative studies on the effects1 of acrylamide and related analogues
Compound                 Neuro-      Testicular  Lethality    Reactivity     Decrease in concentration of    
and formula              toxicity2   atrophy2    (mg/kg)      with           of non-protein sulfhydrylsb     
                                                 (oral LD50)  glutathioned   Brain      Liver      Testes    
acrylamide               (+)a,b,d,i  (+)b,i      see Table 7  0.91           (-)        (+)        (+)       
CH2 = CHCONH2                                                                                            
methyl acrylate                                  825e, 200f                                              
CH2 = CHCO2CH3                                   (rabbit)                                                 
sodium acrylate          (-)a                                                                             
CH2 = CHCO2Na                                                                                             
 N-methylacrylamide       (+)a,b,d,i  (+)b,i      480b, 477i   0.058          (+)        (-)        (+)       
CH2 = CHCONHCH3                                                                                           
 N-ethylacrylamide        (+)c                                                                             
CH2 = CHCONHC2H5                                                                                          
 N-hydroxymethyl-         (+)b,d,i,   (+)b,i      560b, 576i   0.91           (-)        (+)        (+)       
 acrylamide              ()a, (-)g                                                                       
CH2 = CHCONHCH2OH                                                                                         
 N-isopropylacrylamide    (+)b,i      (+)i, (-)b  350b, 419i                  (-)        (-)        (-)       
CH2 = CHCONHCH(CH3)2                                                                                      
 N,N '-dimethylacrylamide (-)b        (-)b,i      675b, 677i                  (-)        (-)        (-)       
CH2 = CHCON(CH3)2                                                                                            

Table 14.  (contd.)
Compound                 Neuro-      Testicular  Lethality     Reactivity    Decrease in concentration of
and formula              toxicity2   atrophy2    (mg/kg)       with          non-protein sulfhydrylsb
                                                 (oral LD50)   glutathioned  Brain      Liver      Testes
 N,N'-diethylacrylamide   (+)c,d,     (-)b,i      1412b, 1399i  0.058         (-)        (-)        (-)
CH2 = CHCON(C2H5)2       (-)a,b                                            
Methacrylamide           (+)b,i,     (-)b,i      600b, 451i    
CH2 = C(CH3)CONH2        (-)a                                              
 N-methylmethacrylamide   (-)c                                              
CH2 = C(CH3)CONHCH3                                                        
Crotonamide              (-)a,b      (-)b,i      512b, 2724i                 (-)        (-)        (-)
CH(CH3) = CHCONH2                                                          
Senecioic acid amide     (-)a                                              
(CH3)2C = CHCONH2                                                          
Allyl acetamide          (-)a                                              
CH2 = CHCH2CONH2                                                           
 N,N'-methylene-          (-)b,h      (+)b,i      399b, 401i    0.54          (-)        (-)        (-)
(CH2 = CHCONH)2CH2                                                         
Acrylonitrile            (-)a                                              
CH2 = CHCN                                                     
1  Effects in rats and/or mice unless stated.                                                  
2  For dosing schedules/relative toxicities, refer to primary references.                                          
a  From: Barnes (1970).                    
b  From: Hashimoto & Sakamoto (1979).
c  From: Benesova (1979).
d  From: Edwards (1975b).
e  From: Tanii & Hasimoto (1982).
f  From: Autian (1975).
g  From: Hashimoto & Aldridge (1978).
h  From: Schotman et al. (1978).
i  From: Hashimoto et al. (1981).
(+) denotes positive or significant effect.
(-) denotes absence of or insignificant effect.
    Hashimoto et al. (1981) studied the effects of orally-
administered acrylamide and analogues on the nervous system in
mice.  Of 14 analogues tested, 5 produced neuropathy.  In
decreasing order of potency (as assessed by the rotarod
performance test), these were: acrylamide >  N -isopropyl-
acrylamide >  N -methylacrylamide > methacrylamide >
 N -hydroxymethylacrylamide.  Mice treated with these compounds
gradually showed signs of weakness and ataxia of hind limbs,
with symptoms of slight behavioural changes such as aggres-
siveness and alertness (Hashimoto et al., 1981).  Four
neurotoxic compounds (acrylamide,  N -hydroxymethylacrylamide,
 N -isopropylacrylamide, and  N -methylacrylamide) and 1 non-
neurotoxic compound ( N,N -methylenebisacrylamide (MBA))
produced both atrophy and a significant reduction in the
weight of the testis.  Only 1 compound,  N -isopropylacrylamide,
seemed to be toxic by virtue of its biotransformation to
acrylamide (Tanii & Hashimoto, 1981).  This compound also 
produced marked effects on red and white blood cell counts, 
haemoglobin concentration, and haematocrit values in both rats 
and mice (Hashimoto et al., 1981; Hashimoto & Sakamoto, 1982).  
Urinary porphyrins were elevated and ALA-D activity decreased in 
rats after MBA-dosing, the origins of which seemed to be mainly 
erythropoietic rather than hepatic. Similarly, a marked increase 
in hepatic porphyrins was reported after subcutaneous 
administration of 2-allyl-2-isopropyl-acetamide (Edwards et al., 
1978).  MBA has been commonly used in chemical grouting and 
chromatography, and has been identified as a component in photo-
polymerizing printing plates.  Contact skin allergies have also 
been reported with MBA (Malten et al., 1978) and other secondary 
acrylamide derivatives (Pye & Peachey, 1976; Pedersen et al., 

    Schotman et al. (1978) compared the effects of MBA and 
acrylamide on several neurochemical and behavioural measures. 
Both compounds affected protein synthesis, but only acrylamide 
impaired rotarod performance, suggesting that this mechanism may 
not be related to the neurological effects of acrylamide. 

    The effects of secondary acrylamides on both cell cultures
and rats were investigated by Benesova et al. (1979).  Results
from cell-culture studies indicated that  N -substituted
acrylamides are more toxic than the respective  N -substituted
methacrylamides.  Of the compounds tested in rats,  N -ethyl-
acrylamide was reported to be the most toxic, producing
tonic-clonic convulsions and death after dermal applications.
Similar, but less pronounced, effects were found with
 N,N' -diethylacrylamide (DEAA), indicating that the toxicity of
some  N -substituted methacrylamides is quite considerable,
inducing similar effects to acrylamide.

    Esters of acrylic acid (in particular methyl methacrylate) 
have wide applications in a number of industrial and consumer 
products.  Most of the acrylic acid esters are volatile and can 
produce various levels of toxicity if inhaled.  The toxicity and 
structure-activity relationships of a large number of acrylic 

esters have been investigated (Autian, 1975; Tanii & Hashimoto, 
1982).  Generally, the systemic effects of the lower relative 
molecular mass acrylic monomers are manifested by irregular 
respiration and reduced blood pressure.  With lethal doses, 
reflex activity ceases and the animals die in coma.  Acrylic 
monomers also irritate the skin and mucous membranes.  Data from 
an embryonic-fetal toxicity study indicated that all 4 
methacrylate esters in the study also induced deleterious effects 
on the developing embryo (Autian, 1975) at a daily exposure 
likely to be encountered in an occupational environment. 

    In summary, many analogues and derivatives of acrylamide
have been studied, but only 5 have been reported to exhibit
neurotoxic potential ( N -methylacrylamide,  N -isopropyl-
acrylamide,  N -hydroxymethylacrylamide, methacrylamide, and
 N,N '-diethylacrylamide).  The toxic potential cannot be
attributed solely to the general chemical reactivities with
thiol-containing compounds (e.g., glutathione).  Comparison of
molecular structures has shown that the development of
neurotoxic effects cannot be wholly attributed to any specific
group or molecular conformation.  Substitution or addition of
other groups at either the alpha or  carbon atoms or at the NH2
group of acrylamide decreased the neurotoxicity of the molecule.  
However, other effects may be retained, i.e., effects on protein 
synthesis or testicular damage.  Biotrans-formation of 
 N -isopropylacrylamide to acrylamide has been demonstrated in 
mice.  Such a transformation could account for the elicited 
neurotoxicity of other secondary acrylamides. Completely 
different systemic effects are observed with many other 
acrylamide analogues, e.g., acrylates. 


11.1.  General Considerations

    Epidemiological data related to occupational or environmental 
exposure to acrylamide are insufficient to serve as a basis for 
quantitative risk evaluation (section 8.2). Consequently, this 
evaluation is based on animal studies. 

    Although the complete metabolic profile for acrylamide has 
not been elucidated, there do not appear to be any major species 
differences among mammals.  Manifestations of acrylamide 
poisoning were similar and dose-effect relation-ships (dose as a 
function of body surface area) were also similar for all mammals 
studied (rats, mice, cats, dogs, monkeys, and baboons). 

    In view of the limited human data, it must be assumed that 
the metabolism of acrylamide in man is similar to that in other 
mammalian species, with a comparable dose-effect relationship.  
However, should a metabolite be the primary neurotoxic agent, 
which is likely, then it would be reasonable to assume that 
differences in toxic response might exist, because of differences 
in metabolic profiles between species. Thus, it seems prudent to 
start with the most sensitive species when extrapolating 
quantitative animal data to man. 

    Most long-term exposure studies have been conducted on rats.  
In this species, the lowest daily dose reported to cause definite 
signs of adverse neurological effects was 1 mg acrylamide/kg body 
weight, administered orally for 93 days (Burek et al., 1980).  
For the reasons given in section, these findings need 
confirmation.  However, on the basis of the available long-term 
studies, and taking these caveats into account, it appears that 
the long-term minimal adverse neurological effect level for 
acrylamide lies in the region of 1 mg/kg body weight per day and 
a probable estimated no-effect level is 0.5 mg/kg body weight per 
day in rats. This level is supported by findings from studies 
using functional indices of acrylamide toxicity. 

    Assuming that the toxic dose is related to the metabolic 
rate, which for mammals is related to the body weight by the 
power of 0.76 (Stahl, 1967), the equivalent minimum daily toxic 
dose in a 2 - 4 kg cat can be calculated to be 0.3 -0.2 mg/kg 
body weight.  This figure is consistent with data obtained from 
long-term toxicity studies on cats, where neurological signs, 
unconfirmed morphologically, were observed, in some animals, 
after exposure for 240 days to 1 mg acrylamide/kg body weight per 
day (McCollister et al., 1964). Similarly, extrapolation of these 
data to man (applying the above relationship) provides a figure 
of 0.12 mg/kg body weight per day, which might be expected to 
induce minimal adverse effects in human beings.  The application 
of a safety factor would therefore be required in order to obtain 
an acceptable exposure level. 

    When determining this safety factor, the limitations of the 
derived human exposure level (0.12 mg/kg body weight per day) 
should be realized.  First, this figure has been extrapolated 
from a test group of animals with a rather homogeneous genetic 
background.  Second, a high incidence of possible effects was 
seen in these animal studies.  However, in a human population, an 
incidence of adverse effects below 5% is unlikely to be detected 
in an epidemiological study, and this should be taken into 
account in the extrapolation of animal exposure data to man.  
Third, it is not clear whether the observed morphological changes 
in the peripheral nerves reflect the primary adverse effects.  
For example, acrylamide has been shown to interfere with both 
neurotransmitter concentrations and neuroreceptor densities in 
the brain (section, although it is not possible, on the 
basis of available experimental data, to assess the lowest 
exposure level that induces these effects.  Such effects may, 
however, be secondary to those involved directly in the genesis 
of neuropathy.  Finally, environmental factors may influence the 
toxicity of acrylamide.  For example, both inducers and 
inhibitors of metabolic enzymes have been shown to modify the 
toxicity and metabolism of acrylamide in experimental animals 
(section 6.1.2.). 

    Thus, applying a safety factor of 10 to the estimated minimal 
adverse neurological effect level for human beings would indicate 
a daily intake not exceeding 0.012 mg/kg body weight. 

    It should be emphasized that this value is based solely on 
the neurotoxicity of acrylamide and does not take into account 
the risk of cancer or interference with reproductive capability. 

    No epidemiological data on cancer due to exposure to 
acrylamide are available.  Acrylamide (> 99% pure) was not 
mutagenic in  S. typhimurium,  in the absence or presence of a 
metabolic activation system. 

    Acrylamide of unknown purity induced chromosomal aberrations 
in the spermatocytes of mice and was reported to increase cell 
transformation frequency in Balb 3T3 cells in the presence of a 
metabolic activation system. 

    Acrylamide was shown to be an initiator for skin tumours in 
mice, when administered by various routes, and increased the 
incidence of lung tumours in mice-screening assays. 

    A 2-year study on rats, administered acrylamide in the 
drinking-water, has not been fully evaluated.  It is not possible 
to form any conclusions concerning the carcinogenicity of 
acrylamide on the basis of available data. 

    Acrylamide (10 - 20 mg/kg body weight per day) caused 
testicular degeneration in mice (Shiraishi, 1978; Hashimoto & 
Tanii, 1981) and spermatocyte chromosome aberrations.  A similar 
acrylamide exposure (20 mg/kg body weight per day, for 20 days) 
caused a major depression in the plasma levels of testosterone in 
Fischer 344 rats.  No information is available concerning the 
minimum long-term acrylamide exposure required to elicit such 
effects; thus, it is impossible, at present, to assess the risk 
of acrylamide-induced effects on reproduction in man. 

11.2.  Assessment of Exposure

    Exposure measurements using personal sampling or stationary 
sampling have obvious shortcomings in the assessment of 
occupational exposure, as they do not take absorption through the 
skin into account.  A reasonably accurate measurement of exposure 
will require biological monitoring.  So far, no method for 
biological monitoring has been established, though the results of 
experimental animal studies (Young et al., 1979; Pastoor & 
Richardson, 1981) indicate that the amount of acrylamide bound to 
red blood cells would reflect both the exposure level and the 
accumulated concentration in nervous tissue (section and 

11.3.  Assessment of Adverse Effects

    In any group of "healthy" individuals, a small proportion 
will have some abnormal neurological symptoms or signs.  This 
makes it difficult to assess the significance of minor clinical 
neurological abnormalities in any one individual.  In an 
epidemiological study, incidence of abnormalities in a group of 
subjects exposed to acrylamide can be compared with the incidence 
in a group of unexposed subjects.  The same arguments may be 
applied to the results of electrophysio-logical tests, where the 
range of values in control subjects is wide.  To obtain maximum 
sensitivity, pre-exposure, base-line observations are most 

    Clinical experience has shown that the most sensitive 
electrophysiological parameter is the measurement of sensory 
nerve action potential amplitude in the distal part of a limb 
(section 8.1.). 

    Arezzo et al. (1983) have described the use of a quantitative 
measure of the threshold of vibration sensation in the fingers to 
screen acrylamide-exposed workers.  Earlier neurological 
abnormalities would be detected by testing the toes.  This method 
has great potential as it is sensitive, quick, and can be used in 
the field.  Equipment for measuring vibration threshold is 
available commercially.  A recent extensive survey of vibration 
threshold measurements in a large number of healthy individuals 
of different ages using a biothesiometer has been published.  
This type of assessment has proved useful in assessing other 
peripheral nerve diseases, e.g., diabetes.  In applying such 
techniques, a sensitive method of psychophysical assessment must 

be used, e.g., using a type of forced choice procedure to avoid 
undue bias in the results.  Encouragement to pursue this type of 
assessment is provided by the positive results obtained by 
Maurissen et al. (1983) using a similar procedure in monkeys 
(section 7.1.1.). 

    Animal experience indicates that sensory and visual evoked 
potentials are useful indications of acrylamide interference in 
central nervous system function (section 

11.4.  Exposure of the Environment

    The use of acrylamide as a grouting agent has proved to be 
the greatest potential hazard for man, due to contamination of 
ground water.  Such contamination led to an incident of 
acrylamide poisoning in Japan when well water became polluted 
with acrylamide (400 mg/litre) from a grouting operation (2.5 
metres away) that had taken place 1 month before (section 
5.1.2.).  Special precautions must therefore be taken to limit 
ground water contamination and, if it becomes contaminated, to 
prevent its consumption. 

    Some effluents from the dewatering processes of industrial 
and communal sewage plants and water works have been found to 
contain between < 1 - 45 g acrylamide/litre (section 5.1.2.). 
Levels of acrylamide in effluent-receiving waters are highly 
variable because of dilution factors.  The highest reported level 
is 1.5 mg/litre (section 5.1.2.).  Novikova (1979) estimated the 
maximum safe daily level of acrylamide that could be absorbed by 
the hands, from hand-washing water, to be 3.5 mg, assuming that 
the hands constitute 5% of the total surface area of the human 
body.  This figure was derived from the results of a long-term 
dermal toxicity study on rats where 5% of the body surface area 
(tail) was exposed to different concentrations of acrylamide with 
a safety factor of 10 applied to the dose at which no adverse 
effects were observed (section  For swimming, with an 
acrylamide concentration of 5 g/litre in the water, a total 
clearance of more than 700 litres would be required (via skin 
absorption) to exceed the safety threshold of 3.5 mg.  However, 
at levels of 1 mg/litre in the water, a clearance of less than 5 
litres would be needed.  Repeated or daily swimming in waters 
contaminated with acrylamide at such a concentration may present 
a health hazard. 

11.5.  Occupational Exposure

    Experience has clearly shown that occupational exposure to 
acrylamide can present a hazard for workers, through dermal 
absorption or inhalation, or both.  As acrylamide is readily 
absorbed through the skin, workers should be protected by 
suitable protective clothing or by enclosing production 
procedures to ensure minimum exposure.  To prevent inhalation, 
ventilated face masks may be necessary.  Recommended occupational 
exposure levels for acrylamide in workroom air for a number of 
countries are listed in Table 5. 

    It is possible that underlying neurological disease and/or 
the administration of neuroactive drugs might alter the 
sensitivity of man to acrylamide and, this should be borne in 
mind for workers.  However, in the absence of definite evidence 
that this has occurred, no specific recommendation to exclude 
such workers from contact with acrylamide processes can be made. 


ABDELMAGID, H.M. & TABATABAI, M.A.  (1982)  Decomposition of
acrylamide in soils.  J. environ. Qual., 11(4): 701-704.

ACGIH  (1974)   "Acrylamide" documentation of the threshold
 limit values for substances in workroom air, 3rd ed.,
Cincinnati, Ohio, American Conference of Governmental
Industrial Hygienists.

ACGIH  (1984)   Threshold limit values for chemical substances
 and physical agents in the work environment and biological
 indices with intended changes for 1984-85, Cincinnati, Ohio,
American Conference of Governmental and Industrial Hygienists.

AGRAWAL, A.K. & SQUIBB, R.E.  (1981)  Effects of acrylamide
given during gestation on dopamine receptor binding in rat
pups.  Toxicol. Lett., 7: 233-238.

UPHOUSE, L.L., & BONDY, S.C.  (1981a)  Neurotransmitter
receptors in brain regions of acrylamide-treated rats. I.
Effects of a single exposure to acrylamide.  Pharmacol.
 Biochem. Behav., 14: 527-531.

AGRAWAL, A.K., SQUIBB, R.E., & BONDY, S.C.  (1981b)  The
effects of acrylamide treatment upon the dopamine receptor.
 Toxicol. appl. Pharmacol., 58: 89-99.

ALDOUS, C.N., SHARMA, R.P., & FARR, C.H.  (1981)  Acrylamide
effects on catecholamine metabolism.  Toxicologist, 1: 52.

AMERICAN CYANAMID  (1961)   Chemistry of acrylamide, New York,
Cyanamide International, 43 pp.

Conditioned taste aversion following acutely administered
acrylamide.  Neurobehav. Toxicol. Teratol., 4: 497-499.

ANDERSON, R.J.  (1981)  Selective effect on peripheral nerves
after subchronic administration of acrylamide.  Bull. environ.
 Contam. Toxicol., 27: 888-893.

ANDERSON, R.J.  (1982)  Alterations in nerve and muscle
compound action potentials after acute acrylamide
administration.  Environ. Health Perspect., 44: 153-157.

ANDO, K. & HASHIMOTO, K.  (1972)  Accumulation of [14C]-
acrylamide in mouse nerve tissue. In:  Proceedings of the Osaka
 Prefectural Institute of Public Health, Vol. 10, pp. 7-12.

ANON  (1967)  Acrylamide poisoning reports on work hygiene
branch of Kangawa labour standards office.  Roco osei, 8: 68-69.

ARAI, T., KURODA, S., & WATANABE, I.  (1981)  Biodegradation
of acrylamide monomer by a rhodococcus strain. In: Schaal,
K.P. & Pulverer, G., ed.  Actinomycetes, Stuttgart, Gustav
Fischer Verlag, pp. 297-307.

P.S., & BARNA, J.  (1982)  Hind limb somatosensory evoked
potentials in the monkey: The effects of distal axonopathy.
 Ann. Neurol., 12: 24-32.

Rapid screening for peripheral neuropathy: A field study with
the Optacon.  Neurology, 33: 626-629.

ASBURY, A.K., COX, S.C., & KANADA, D.  (1973)  3H-leucine
incorporation in acrylamide neuropathy in the mouse.
 Neurology, 23: 406.

AULD, R.B. & BEDWELL, S.F.  (1967)  Peripheral neuropathy with
sympathetic overactivity from industrial contact with
acrylamide.  Can. Med. Assoc. J., 96(11): 652-654.

AUTIAN, J.  (1975)  Structure-toxicity relationships of
acrylic monomer.  Environ. Health Perspect., 11: 141-152.

AZZAM, R.A.I.  (1980)  Agricultural polymers: Polyacrylamide
preparation, application, and prospects in soil conditioning.
 Soil Sci. plant Anal., 11(8): 767-834.

BARNES, J.M.  (1970)  Observations on the effects on rats of
compounds related to acrylamide.   Br. J. ind. Med., 27:

(1979)  Biological effects of some N-substituted
(meth)acrylamides.  Polym. Med., 9: 63-68.

BETSO, S.R. & MCLEAN, J.D.  (1976)  Determination of
acrylamide monomer by differential pulse polarography.  Anal.
 Chem., 48(4): 766-770.

BIKALES, N.M.  (1973)  Preparation of acrylamide polymers. In:
Bikales, N.M., ed.  Polymer science and technology, New York,
Plenum Press, Vol. 2, pp. 213-222.

BILDERBACK, D.E.  (1981)  Impatiens pollen germination and
tube growth as a bioassay for toxic substances.  Environ.
 Health Perspect., 37: 95-103.

BLACKFORD, J.L.  (1974)  In:  Chemical economics handbook,
Menlo Park, California, Standford Research Institute, p. 607
(5031 A-607.5033G).

BONDY, S.C., TILSON, H.A., & AGRAWAL, A.K.  (1981)
Neurotransmitter receptors in brain regions of acrylamide-
treated rats. II. Effects of extended exposure to acrylamide.
 Pharmacol. Biochem. Behav., 14: 533-537.

BOYES, W.K. & COOPER, G.P.  (1981)  Acrylamide neurotoxicity:
Effects on far-field somatosensory evoked potentials in rats.
 Neurobehav. Toxicol. Teratol., 3: 487-490.

BRADLEY, W.G. & ASBURY, A.K.  (1970)  Radioautographic studies
of Schwann cell behaviour. I. Acrylamide neuropathy in the
mouse.  J. Neuropathol. exp. Neurol., 29: 500-506.

BRADLEY, W.G. & WILLIAMS, M.H.  (1973)  Axoplasmic flow in
axonal neuropathies. I. Axoplasmic flow in cats with toxic
neuropathies.  Brain, 96: 235-246.

BRIDIE, A.L., WOLFF, C.J.M., & WINTER, M.  (1979a)  BOD and
COD of some petrochemicals.  Water Res., 13: 627-630.

BRIDIE, A.L., WOLFF, C.J.M., & WINTER, M.  (1979b)  Acute
toxicity of some petrochemicals to goldfish.  Water Res., 13:

BROWN, L. & RHEAD, M.  (1979)  Liquid chromatographic
determination of acrylamide monomer in natural and polluted
aqueous environments.  Analyst, 104: 391-399.

(1980a)  Model studies of the degradation of acrylamide
monomer.  Water Res., 14: 775-778.

BROWN, L., RHEAD, M.M., & BANCROFT, K.C.C.  (1980b)  Case
studies of acrylamide pollution resulting from the industrial
use of polyacrylamides.  Water Pollut. Control, 79: 507-510.

BROWN, L., BANCROFT, K.C.C., & RHEAD, M.M.  (1980c)
Laboratory studies on the adsorption of acrylamide monomer by
sludge, sediments, clays, peat, and synthetic resins.  Water
 Res., 14: 779-781.

BROWN, L., RHEAD, M.M., HILL, D., & BANCROFT, K.C.C.  (1982)
Qualitative and quantitative studies on the in situ
adsorption, degradation, and toxicity of acrylamide by the
spiking of the waters of two sewage works and a river.  Water
 Res., 16: 579-591.

GREISIGER, E., MEIER, J.R., & STOBER, J.  (1984)  Carcinogenic
effects of acrylamide in Sencar and A/J mice.   Cancer Res.,
44: 107-111

S.J.  (1980)  Subchronic toxicity of acrylamide administered
to rats in the drinking-water followed by up to 144 days of
recovery.  J. environ. Pathol. Toxicol., 4: 157-182.

CABE, P.A. & COLWELL, P.B.  (1981)  Toxic effects of
acrylamide in Japanese quail.  J. Toxicol. environ. Health, 7:

CAVANAGH, J.B.  (1982)  The pathokinetics of acrylamide
intoxication: A reassessment of the problem.  Neuropathol.
 appl. Neurobiol., 8: 315-336.

CAVANAGH, J.B. & GYSBERS, M.F.  (1981)  Ultrastructural
changes in axons caused by acrylamide above a nerve ligature.
 Neuropathol. appl. Neurobiol., 7: 315-326.

CAVANAGH, J.B. & GYSBERS, M.F.  (1983)  Ultrastructural
features of the Purkinje cell damage caused by acrylamide in
the rat: A new phenomenon in cellular neuropathology.  J.
 Neurocytol., 12: 413-437.

CAVIGNEAUX, A. & CABASSON, G.B.  (1971)  Intoxication par
l'acrylamide.  Arch. Mal. prof. Md. Trav. Scur. soc., 33:

CHERRY, A.B., GABACCIA, A.J., & SENN, H.W.  (1956)  The
assimilation behavior of certain toxic organic compounds in
natural water.  Sewage ind. Wastes, 28: 1137-1146.

CHRETIEN, M., PATEY, G., SOUYRI, F., & DROZ, B.  (1981)
"Acrylamide-induced" neuropathy and impairment of axonal
transport of proteins. II. Abnormal accumulation of smooth
endoplasmic reticulum as sites of focal retention of fast
transported proteins. Electron microscope radioautographic
study.  Brain Res., 205: 15-28.

J.G., & CARTER, J.W.  (1979)   Assessment of the need for and
 character of limitations on acrylamide and its compounds,
Washington DC, US Environmental Protection Agency (Report
prepared for the Office of Pesticides and Toxic Substances,
Contract No. 68-10-4308).

& FARDEAU, M.  (1982)  Acrylamide neuropathy and changes in
the axonal transport and muscular content of the molecular
forms of acetylcholinesterase.  Muscle Nerve, 5: 302-312.

CROLL, B.T. & SIMKINS, G.M.  (1972)  The determination of
acrylamide in water by using electron-capture gas
chromatography.  Analyst, 97: 281-288.

CROLL, B.T., ARKELL, G.M., & HODGE, R.P.J.  (1974)  Residues
of acrylamide in water.  Water Res., 8: 989-993.

P.S.  (1981)  Protective effect of sodium pyruvate on
acrylamide-induced neuropathy in rats.  Toxicologist, 1: 52.

DAS, M., MUKHTAR, H., & SETH, P.K.  (1982)  Effect of
acrylamide on brain and hepatic mixed-function oxidases and
glutathione-S-transferase in rats.  Toxicol. appl. Pharmacol.,
66: 420-426.

DAVENPORT, J.G., FARRELL, D.F., & SUMI, S.M.  (1976)  "Giant
axonal neuropathy" caused by industrial chemicals:
Neurofilamentous axonal masses in man.  Neurology, 26: 919-923.

DAVIS, L.N., DURKIN, P.R., & HOWARD, P.H.  (1976)
 Investigation of selected potential environmental
 contaminants: Acrylamides, Washington DC, US Environmental
Protection Agency, 159 pp (EPA Report No. 560/2-76-008, PB

DIXIT, R., HUSAIN, R., SETH, P.K., & MUKHTAR, H.  (1980a)
Effect of diethyl maleate on acrylamide induced neuropathy in
rats.  Toxicol. Lett., 6(6): 417-421.

(1980b)  Binding of acrylamide with glutathione-S-
transferases.  Chem.-biol. Interact., 32: 353-359.

(1981a)  Conjugation of acrylamide with glutathione catalysed
by glutathione-S-transferases of rat liver and brain.  Biochem.
 Pharmacol., 30(13): 1739-1744.

DIXIT, R., HUSAIN, R., MUKHTAR, H., & SETH, P.K.  (1981b)
Acrylamide induced inhibition of hepatic glutathione- S-
transferase activity in rats.  Toxicol. Lett., 7: 207-210.

DIXIT, R., HUSAIN, R., MUKHTAR, H., SETH, P.K.  (1981c)
Effect of acrylamide on biogenic amine levels, monoamine
oxidase, and cathepsin D activity of rat brain.  Environ. Res.,
26: 168-173.

DIXIT, R., SETH, P.K., & MUKHTAR, H.  (1982)  Metabolism of
acrylamide into urinary mercapturic acid and cysteine
conjugates in rats.  Drug Metab. Dispos., 10: 196-197.

DREES, D.T., CRAGO, F.L., HOPPER, C.R., & SMITH, J.M.  (1976)
Subchronic percutaneous toxicity of acrylamide and
methacrylamide in the new-born rabbit.  Toxicol. appl.
 Pharmacol., 37: 190.

DRUCKERY, H., CONSBRUCH, U., & SCHMAHL, D.  (1953)  [Effects
of monomeric acrylamide on proteins.]  Naturforsch., 8(b):
145-150 (in German).

ECT  (1978)   Encyclopedia of chemical technology, 3rd ed.,
Vol. 1, pp. 302-306.

EDWARDS, P.M.  (1975a)  The distribution and metabolism of
acrylamide and its neurotoxic analogues in rats.  Biochem.
 Pharmacol., 24: 1277-1282.

EDWARDS, P.M.  (1975b)  Neurotoxicity of acrylamide and its
analogues and the effects of these analogues and other agents
on acrylamide neuropathy.  Br. J. ind. Med., 32: 31-38.

EDWARDS, P.M.  (1976a)  The insensitivity of the developing
rat fetus to the toxic effects of acrylamide.  Chem.-biol.
 Interact., 12: 13-18.

EDWARDS, P.M.  (1976b)   UK Council for National Academy Awards
(Thesis for PhD degree).

EDWARDS, P.M. & PARKER, V.H.  (1977)  A simple and objective
method for early assessment of acrylamide neuropathy in rats.
 Toxicol. appl. Pharmacol., 40: 589-591.

EDWARDS, P.M., FRANCIS, J.E., & DE MATTEIS, F.  (1978)  The
glutathione-linked metabolism of 2-allyl-2-isopropylacetamide
in rats. Further evidence for the formation of a reactive
metabolite.  Chem.-biol. Interact., 23: 233-241.

ERICSSON, A.-C. & WALUM, E.  (1984)  Cytotoxicity of
cyclophosphamide and acrylamide in glioma and neuroblastoma
cell lines cocultured with liver cells.  Toxicol. Lett., 20:

FARR, C.H., SHARMA, R.P., & ALDOUS, C.N.  (1981)  Acrylamide
neurotixicity: Levels of tryptophan, serotonin, and 5-hydroxy-
indole-acetic acid and serotonin turnover in rat brain.
 Toxicology, 1: 52-53.

BONDY, S.C.  (1983)  Effect of acrylamide on neurotransmitter
metabolism and neuropeptide levels in several brain regions
and upon circulating hormones.  Arch. Toxicol., 52: 35-43.

SUZUKI, E., NAKAZAWA, T., & TAKAHASHI, T.  (1960)  [Clinical
observations of three cases of acrylamide poisoning.]  Nippon
 Ijo Shimpo, 1869: 37-40 (in Japanese).

FULLERTON, P.M.  (1969)  Electrophysiological and histological
observations on peripheral nerves in acrylamide poisoning in
man.  J. Neurol. Neurosurg. Psychiatr., 32: 186-192.

FULLERTON, P.M. & BARNES, J.M.  (1966)  Peripheral neuropathy
in rats produced by acrylamide.  Br. J. ind. Med., 23: 210-221.

GARLAND, T.O. & PATTERSON, M.W.H.  (1967)  Six cases of
acrylamide poisoning.  Br. med. J., 4: 134-138.

GHIRINGHELLI, L.  (1956)  [Comparative study on the toxicity
of some nitriles and of some amides.]  Med. Lav., 47: 1-8 (in

GILBERT, S.G. & MAURISSEN, J.P.J.  (1982)  Assessment of the
effects of acrylamide, methylmercury, and 2,5-hexanedione on
motor functions in mice.  J. Toxicol. environ. Health, 10:

(1977)  Polyneuropathies and CNS protein metabolism. I.
Description of the acrylamide syndrome in rats.  Neuropathol.
 appl. Neurobiol., 3: 115-123.

GOING, J.E.  (1978)   Environmental monitoring near industrial
 sites, Washington DC, US Environmental Protection Agency (EPA
Contract No. 560/6-78-001, PB 281 879).

GOING, J.E. & THOMAS, K.  (1979)   Sampling and analysis of
 selected toxic substances. Task I. Acrylamide, Washington DC,
US Environmental Protection Agency (EPA Contract No.
560/13-79-013, PB 80-128150).

GOLDSTEIN, B.D. & LOWNDES, H.E.  (1979)  Spinal cord defect in
the peripheral neuropathy resulting from acrylamide.
 Neurotoxicology, 1: 75-87.

Polyneurite cause par l'acrylamide.  Rev. neurol. (Paris),
123: 62-65.

GRIFFIN, J.W., PRICE, D.L., & DRACHMAN, D.B.  (1977)  Impaired
axonal regeneration in acrylamide intoxication.  J. Neurobiol.,
8(4): 355-370.

HACKADAY, T.D.R., HILLSON, R.M., & SMITH, B.  (1982)
Correlates of deterioration in pedal vibration sensory
threshold over 5 years from diagnosis of maturity onset in
diabetic patients.  Diabetologia, 23: 174.

HAMBLIN, D.O.  (1956)  The toxicity of acrylamide: A
preliminary report. In:  Hommage au Doyen Ren Fabre (Paris),
pp. 195-199.

HANSCH, C. & LEO, A.  (1979)   Substituent constants for
 correlation analysis in chemistry and biology, New York, John
Wiley and Sons, 336 pp.

HASHIMOTO, K.  (1980)  [The toxicity of acrylamide.]  Jap. J.
 ind. Health, 22: 233-248 (in Japanese).

HASHIMOTO, K. & ALDRIDGE, W.N.  (1970)  Biochemical studies on
acrylamide, a neurotoxic agent.  Biochem. Pharmacol., 19:

HASHIMOTO, K. & ANDO, K.  (1971)  [Studies on acrylamide
neuropathy. Effects of the permeability of amino acids into
nervous tissue; distribution and metabolism.] In:  Proceedings
 of the Osaka Prefectoral Institution, Public Health Education
 and Industrial Health, Vol. 9, pp. 1-4 (in Japanese).

HASHIMOTO, K. & ANDO, K.  (1973)  Alteration of amino acid
incorporation into proteins of the nervous system in vitro
after administration of acrylamide to rats.  Biochem.
 Pharmacol., 22: 1057-1066.

HASHIMOTO, K. & ANDO, K.  (1975)  Studies on the percutaneous
absorption of acrylamide. In:  Abstracts of the 18th
 International Congress on Occupational Health, Brighton,
 England, pp. 453.

HASHIMOTO, K. & SAKAMOTO, J.  (1979)  In:  Collected Lectures
 from the 52nd Conference of the Japanese Industrial Hygiene
 Society, pp. 306-307.

HASHIMOTO, K. & SAKAMOTO, J.  (1982)  Anemia and porphyria
caused by  N,N' -methylenebisacrylamide (MBA) in mice and rats.
 Arch. Toxicol., 50: 47-55.

HASHIMOTO, K. & TANII, H.  (1981)  [Percutaneous absorption of
14C-methacrylamide.] In:  Abstracts of the 54th Annual Meeting
 of the Japan Association of Industrial Health, pp. 314-315 (in

Neurotoxicity of acrylamide and related compounds and their
effects on male gonads in mice.  Arch. Toxicol., 47: 179-189.

S.C.  (1982)  Postsynaptic location of acrylamide-induced
modulation of striatal 3H-spiroperiodol binding.
 Neurotoxicology, 3: 108-112.

(1980)  Sensitivity of several cell systems to acrylamide.
 Toxicology, 17(2): 161-167.

HOPKINS, A.P.  (1970)  The effect of acrylamide on the
peripheral nervous system of the baboon.  J. Neurol. Neurosurg.
 Psychiatr., 33: 805-816.

HOPKINS, A.P. & GILLIATT, R.W.  (1971)  Motor and sensory
nerve conduction velocity in the baboon: Normal values and
changes during acrylamide neuropathy.  J. Neurol. Neurosurg.
 Psychiatr., 34: 415-426.

HOWLAND, R.D.  (1981)  The etiology of acrylamide neuropathy:
enolase, phosphofructokinase, and glyceraldehyde-3-phosphate
dehydogenase activities in peripheral nerve, spinal cord,
brain, and skeletal muscle of acrylamide-intoxicated cats.
 Toxicol. appl. Pharmacol., 60: 324-333.

(1980)  The etiology of toxic peripheral neuropathies:  In vivo
effects of acrylamide and 2,5-hexanedione on brain enolase and
other glycolytic enzymes.  Brain Res., 202: 131-142.

J.  (1982)  Tissue lipids in acute acrylamide intoxicated
rats.  J. Can. neurol. Sci., 9(2): 181-184.

HUNGARY, STATE MINISTRY OF HEALTH  (1978)   Hungarian standard
 MSZ No. 21461-78, The Office of Standards of the Hungarian
Republic, State Ministry of Health, Hungary.

IARC  (1979)   Acrylamide, Lyons, International Agency for
Research on Cancer, pp. 73-113 (IARC Monographs on the
Evaluation of the Carcinogenic Risk of Chemicals to Humans,
Supplement 19).

KUROIWA, Y.  (1975)  Acrylamide encephaloneuropathy due to
well water pollution.  J. Neurol. Neurosurg. Psychiatr., 38:

LEVIN, S.  (1983)  Distribution of 14C-labelled acrylamide and
betaine in foetuses of rats, rabbits, beagle dogs, and
miniature pigs.  Food Chem. Toxicol., 21(1): 49-58.

ILO  (1980)   Occupational exposure limits for airborne toxic
 substances, Geneva, International Labour Organisation, 290 pp.

INOMATA, J.  (1967)  Nervous symptoms and kinetics of
porphyrin and acetyl co-enzyme A, especially on the basis of
changes in toxic nerve disturbances.  J. Jpn. Organneurosis
 Soc., 69: 490-516.

IRPTC  (1983)   Legal file, Geneva, International Register of
Potentially Toxic Chemicals, United Nations Environment

ISMAILOVA, S.K.  (1966)  [Suppression of the development of
plant tumours (tomato cancer) by inhibitors of free radicals.]
 Mater. Sess. Zakavkaz. Sov. Koord. Nauch-Issied. Rab. Zasch.
 Rast., pp. 412-415 (in Russian).

JAKOBSEN, J. & SIDENIUS, P.  (1983)  Early and dose-dependent
decrease of retrograde axonal transport in acrylamide-
intoxicated rats.  J. Neurochem., 40(2): 447-454.

JAMES, K.A.C., BRAY, J.J., MORGAN, I.G., & AUSTIN, L.  (1970)
The effect of colchicine on the transport of axonal protein in
the chicken.  Biochem. J., 117: 767-771.

JOHNSON, E.C. & MURPHY, S.D.  (1977)  Effect of acrylamide
intoxication on pyridine nucleotide concentrations and
functions in rat cerebral cortex.  Biochem. Pharmacol., 26:

R.A.  (1984)   Acrylamide:  A two-year drinking water chronic
 toxicity-oncogenicity study in Fischer 344 rats. Final report,
Michigan, USA, Dow Chemical Company, 257 pp.

(1979)  Comparison of neurobehavioural effects induced by
various experimental models of ataxia in the rat.  Neurobehav.
 Toxicol., 1(Suppl. 1): 175-178.

(1979)  Embryotoxicity of acrolein, acrylonitrile, and
acrylamide in developing chick embryos.  Toxicol. Lett., 4:

KAPLAN, M.L. & MURPHY, S.D.  (1972)  Effects of acrylamide on
rotarod performance and sciatic nerve beta-glucoronidase
activity of rats.  Toxicol. appl. Pharmacol., 22: 259-268.

KAPLAN, M.L., MURPHY, S.D., & GILLIES, F.H.  (1973)
Modification of acrylamide neuropathy in rats by selected
factors.  Toxicol. appl. Pharmacol., 24: 564-579.

KEMPLAY, S. & CAVANAGH, J.B.  (1983)  Effects of acrylamide
and botulinum toxin on horseradish perioxidase labelling of
trigeminal motor neurons in the rat.  J. Anat., 137(3): 477-482.

KEMPLAY, S. & CAVANAGH, J.B.  (1984)  Effects of acrylamide
and some other sulfhydryl reagents on spontaneous and
pathologically-induced terminal sprouting from motor
end-plates.  Muscle Nerve, 7: 101-109.

KESSON, C.M., LAWSON, D.H., & BAIRD, A.W.  (1977)  Acrylamide
poisoning.  Postgrad. med. J., 53: 16-17.

KOZLOV, Y.P. & DOBRINA, S.K.  (1966)  [Effect of acrylamide
and its hydrated derivative on the E.P.R. spectrum and growth
of normal and tumour tissues in animals.]  Biofizika, 11(1):
168-170 (in Russian).

KUPERMAN, A.S.  (1957)   The pharmacology of acrylamides,
Ithaca, New York, Cornell University Graduate School, 86 pp.

KUPERMAN, A.S.  (1958)  Effects of acrylamide on the central
nervous system of the cat.  J. Pharmacol. exp. Ther., 123:

LANDE, S.S., BOSCH, S.J., & HOWARD, P.H.  (1979)  Degradation
and leaching of acrylamide in soil.  J. environ. Qual., 8(1):

LE QUESNE, P.M.  (1978)  Clinical expression of neurotoxic
injury and diagnostic use of electromyography.  Environ. Health
 Perspect., 26: 89-95.

LE QUESNE, P.M.  (1980)  Acrylamide. In: Spencer, P.S. &
Schaumburg, H.H., ed.  Experimental and clinical
 neurotoxicology, Baltimore, Maryland, Williams & Wilkins
Company, p. 309.

LESWING, R.J. & RIBELIN, W.E.  (1969)  Physiologic and
pathologic changes in acrylamide neuropathy.  Arch. environ.
 Health, 18: 22-29.

TARDIFF, R.G.  (1978)  Effects of low-level exposure to
acrylamide in water on spontaneous locomotor activity.
 Toxicol. appl. Pharmacol., 45(1): 251.

LIJINSKY, W. & ANDREWS, A.W.  (1980)  Mutagenicity of vinyl
compounds in  Salmonella typhimurium. Teratog. Carcinog.
 Mutagen., 1: 259-267.

LOEB, A.L. & ANDERSON, R.J.  (1981)  Antagonism of acrylamide
neurotoxicity by supplementation with vitamin B6.
 Neurotoxicology, 2: 625-633.

LOWNDES, H.E., BAKER, T., CHO, E.S., & JORTNER, B.S.  (1978)
Position sensitivity of de-afferented muscle spindles in
experimental acrylamide neuropathy.  J. Pharmacol. exp. Ther.,
205(1): 40-48.

MCCOLLISTER, D.D., OYEN, F., & ROWE, V.K.  (1964)  Toxicology
of acrylamide.  Toxicol. appl. Pharmacol., 6: 172-181.

MCKIM, J.M. & ANDERSON, R.L.  (1976)  Water pollution: Effects
of pollution on freshwater fish.  J. Water Pollut. Control
 Fed., 48(6): 1544-1620.

MACWILLIAMS, D.C.  (1973)  Acrylamide and other a, -
unsaturated amides. In: Yocum & Nygvist, ed.  Functional

Polarographic and spectrophotometric determination of
acrylamide in acrylamide polymers and copolymers.  Anal. Chem.,
37: 1546-1552.

Nyloprint-sensitive patients react to  N,N '-methylenebis-
acrylamide.  Contact Dermatitis, 4: 214-222.

(1977)  [Neuropathy due to acrylamide: First observations in
Italy.]  Med. Lav., 68(1): 1-12 (in Italian).

MATTOCKS, A.R.  (1968)  Spectrophotometric determination of
pyrazolines and some acrylic amides and esters.  Anal. Chem.,
40(8): 1347-1399.

MAURISSEN, J.P.J., WEISS, B., & DAVIS, H.T.  (1983)
Somatosensory thresholds in monkeys exposed to acrylamide.
 Toxicol. appl. Pharmacol., 71: 266-279.

Acrylamide-induced visual impairment in primates.  Toxicol.
 appl. Pharmacol., 62: 342-345.

METCALF, R.L., LU, P.-Y., & KAPOOR, I.P.  (1973)
 Environmental distribution and metabolic fate of key
 industrial pollutants and pesticides in a "model ecosystem",
Springfield, Virginia, National Technical Information Center,
US Department of Commerce, 80 pp.

MILLER, M.J., CARTER, D.E., & SIPES, I.G.  (1982)
Pharmacokinetics of acrylamide in Fischer-344 rats.  Toxicol.
 appl. Pharmacol., 63: 36-44.

(1983)  Altered retrograde axonal transport of nerve growth
factor after single and repeated doses of acrylamide in the
rat.  Toxicol. appl. Pharmacol., 69: 96-101.

MORI, H.  (1975)  Environmental pollution due to acrylamide
and its toxicity.  Zankoku Kogai Kenkyukai Zasshi, 1: 59-65.

MORIMOTO, M., et al.  (1975)  Poison victims due to acrylamide
mixed with well water at Shingu, Fukuoka Prefecture I. Inquiry
into causes.  Yusui tohaisui, 17: 1307-1318.

MORVILLER, P.  (1969)  Propos sur un toxique industriel peu
connu en France : L'acrylamide.  Arch. Mal. prof. Md. Trav.
 Scur. soc., 30: 527-530.

MUKHTAR, H., DIXIT, R., & SETH, P.K.  (1981)  Reduction in
cutaneous and hepatic glutathione contents, glutathione-S-
transferase, and aryl hydrocarbon hydroxylase activities
following topical application of acrylamide to mouse.  Toxicol.
 Lett., 9: 153-156.

NEELY, W.B., BRANSON, D.R., & BLAU, G.E.  (1974)  Partition
coefficient to measure bioconcentration potential of organic
chemicals in fish.  Environ. Sci. Technol., 8(13): 1113-1115.

GUSTAFSSON, J.-A.  (1978)  Qualitative alterations of
cytochrome P-450 in mouse liver microsomes after
administration of acrylamide and methylmethacrylate.  Acta
 Pharmacol. Toxicol. (Copenhagen), 43: 299-305.

NIOSH  (1976)   Criteria for a recommended standard -
 Occupational exposure to acrylamide, Washington DC, National
Institute for Occupational Safety and Health, 127 pp.

NISHIKAWA, H., HOSOMURA, H., & SONODA, Y.  (1979)  [Behaviour
of acrylamide in soil-plant systems.]  Gifu-Ken Kogyo Gijutsu
 Kenkyu Hokoku, 11: 31-34 (in Japanese).

NORRIS, M.V.  (1967)  Acrylamide. In: Snell, F.D. & Hilton,
C.L., ed.  Encyclopedia of industrial chemical analysis,
Interscience, Vol. 4, pp. 160-168.

NOVIKOVA, E.E.  (1979)  [Toxic effect of acrylamide after
entering through the skin.]  Gig. i Sanit., 10: 73-74 (in

ORTIZ, E., PATEL, J.M., & LEIBMAN, K.C.  (1981)  Specific
inactivation of aniline hydroxylase by a reactive intermediate
formed during acrylamide biotransformation by rat liver
microsomes.  Adv. exp. Med. Biol., 136(B): 1221-1227.

ORTIZ DE MONTELLANO, P.R. & MICO, B.A.  (1980)  Destruction of
cytochrome P-450 by ethylene and other olefins.  Mol.
 Pharmacol., 18: 128.

PASTOOR, T. & RICHARDSON, R.J.  (1981)  Blood dynamics of
acrylamide in rats.  Toxicologist, 1(1): 53.

PASTOOR, T., HEYDENS, W., & RICHARDSON, R.J.  (1980)  Time and
dose-related excretion of acrylamide metabolites in the urine
of Fischer-344 rats. In: Second International Congress on
Toxicology, Brussels, Belgium, 6-11 July.

PAULET, G. & VIDAL, Mme  (1975)  De la toxicit de quelques
esters acryliques et mthacryliques de l'acrylamide et des
polyacrylamides.  Arch. Mal. prof. Md. Trav. Scur. soc., 36:

Secondary acrylamides in nyloprint printing plate as a source
of contact dermatitis.  Contact Dermatitis, 8: 256-262.

PLEASURE, D.E., MISHLER, K.E., & ENGEL, W.K.  (1969)  Axonal
transport of proteins in experimental neuropathies.  Science,
166(3904): 524-525.

POOLE, C.F., SYE, W.F., ZLATKIS, A., & SPENCER, P.S.  (1981)
Determination of acrylamide in nerve tissue homogenates by
electron-capture gas chromatography.  J. Chromatogr., 217:

POST, E.J. & MCLEOD, J.G.  (1977a)  Acrylamide autonomic
neuropathy in the cat. I. Neurophysiological and histological
studies.  J. neurol. Sci., 33: 353-374.

POST, E.J. & MCLEOD, J.G.  (1977b)  Acrylamide autonomic
neuropathy in the cat. Part 2. Effects on mesenteric vascular
control.  J. neurol. Sci., 33: 375-385.

PRINEAS, J.  (1969)  The pathogenesis of dying-back
polyceuropathies. II. An ultrastructural study of experimental
acrylamide intoxication in the cat.  J. Neuropathol. exp.
 Neurol., 28: 598-621.

(1983)  Assessment of chemicals using a battery of
neurobehavioural tests: a comparative study.  Neurobehav.
 Toxicol. Teratol., 5: 91-117.

PTCN  (1983)  Neoplasm rise in high-dose female rats.
 Pesticide and toxic chemical News, 17 August, p. 4.

PYE, R.J. & PEACHEY, R.D.G.  (1976)  Contact dermatitis due to
nyloprint.  Contact Dermatitis, 2: 144-146.

Behavioral and pharmacological responses following acrylamide
exposure in rats.  Neurobehav. Toxicol. Teratol., 4: 355-364.

RASOOL, C.G. & BRADLEY, W.G.  (1978)  Studies on axoplasmic
transport of individual proteins. I. Acetylcholinestrase
(AChE) in acrylamide neuropathy.  J. Neurochem., 31: 419-425.

REFSVIK, T.  (1978)  Excretion of methylmercury in rat bile:
The effect of diethylmaleate, cyclohexene oxide, and
acrylamide.  Acta pharmacol. toxicol. (Copenhagen), 42: 135-141.

SABRI, M.I. & SPENCER, P.S.  (1980)  Toxic distal axonopathy:
Biochemical studies and hypothetical mechanisms. In: Spencer,
P.S. & Schaumburg, H.H., ed.  Experimental and clinical
 neurotoxicity, Baltimore, Maryland, Williams and Wilkins, pp.

SATCHELL, P.M. & MCLEOD, J.G.  (1981)  Megaoesophagus due to
acrylamide neuropathy.  J. Neurol. Neurosurg. Psychiatr., 44:

(1982)  Abnormalities in the vagus nerve in canine acrylamide
neuropathy.  J. Neurol. Neurosurg. Psychiatr., 45: 609-619.

[Three cases of peripheral polyneuropathy due to acrylamide.]
 Clin. Neurol. (Tokyo), 11: 667-672 (in Japanese).

Ultrastructural studies of the dying-back process. I.
Peripheral nerve terminal and axon degeneration in systemic
acrylamide intoxication.  J. Neuropathol. exp. Neurol., 33:

(1977)  Polyneuropathies and CNS protein metabolism. II.
Changes in the incorporation rate of leucine during acrylamide
intoxication.  Neuropathol. appl. Neurobiol., 3: 125-136.

(1978)  Polyneuropathies and CNS protein metabolism. III.
Changes in protein synthesis rate induced by acrylamide
intoxication.  J. Neuropathol. exp. Neurol., 37: 820-837.

SEPPALAINEN, A.M.  (1976)  Applications of neurophysiological
methods in occupational medicine. A review.  Scand. J. Work
 Environ. Health, 1: 1-14.

SHARMA, R.P. & OBERSTEINER, E.J.  (1977a)  Acrylamide
cytotoxicity in chick ganglia cultures.  Toxicol. appl.
 Pharmacol., 42: 149-156.

SHARMA, R.P. & OBERSTEINER, E.J.  (1977b)  Acrylamide effects
of catecholamine metabolism.  Toxicologist, 1(1): 52.

SHIRAISHI, Y.  (1978)  Chromosome aberrations induced by
monomeric acrylamide in bone marrow and germ cells of mice.
 Mutat. Res., 57: 313-324.

SIDENIUS, P. & JAKOBSEN, J.  (1983)  Anterograde axonal
transport in rats during intoxication with acrylamide.  J.
 Neurochem., 40(3): 697-704.

SJOHOLM, I. & EDMAN, P.  (1979)  Acrylic microspheres in vivo.
I. Distribution and elimination of polyacrylamide
microparticles after intravenous and intraperitoneal injection
in mouse and rat.  J. Pharmacol. exp. Ther., 211(3): 656-662.

SKELLY, N.E. & HUSSER, E.R.  (1978)  Determination of
acrylamide monomer in polyacrylamide and in environmental
samples by high performance liquid chromatography.  Anal.
 Chem., 50: 1959-1962.

SONGSON, P., BLOOM, S., TILL, S., & SMITH, R.S.  (1984)  Use
of a biothesiometer to measure individual vibration thresholds
and their variation in 519 non-diabetic subjects.  Br. med. J.,
288: 1793-1795.

SONODA, Y., KANO, K., & HARA, T.  (1977)  [The behaviour of
polyacrylamides as cohesive agent in soil-plant system.] Gifu
 Daigaku Kenkyu Hokoku, 40: 61-69 (in Japanese).

SOUYRI, F., CHRETIEN, M., & DROZ, B.  (1981)  "Acrylamide-
induced" neuropathy and impairment of axonal transport of
proteins. I. Multifocal retention of fast transported proteins
at the periphery of axons as revealed by light microscope
radioautography.  Brain Res., 205: 1-13.

SPENCER, P.S.  (1979)   Unfinished final report, Washington DC,
National Institute for Occupational Safety and Health (NIOSH
Contract No. OH 00535).

SPENCER, P.S. & SCHAUMBURG, H.H.  (1974a)  A review of
acrylamide neurotoxicity. I. Properties, uses, and human
exposure.  J. Can. neurol. Sci., 1: 143-150.

SPENCER, P.S. & SCHAUMBURG, H.H.  (1974b)  A review of
acrylamide neurotoxicity. II. Experimental animal
neurotoxicity and patholgic mechanism.  J. Can. neurol. Sci.,
1: 152-169.

SPENCER, P.S. & SCHAUMBURG, H.H.  (1977)  Ultrastructural
studies of the dying-back process. IV. Differential
vulnerability of PNS and CNS fibres in experimental central-
peripheral distal-peripheral distal axonopathies.  J.
 Neuropathol. exp. Neurol., 36: 300-320.

(1979)  Does a defect in energy metabolism in the nerve fibre
cause axonal degeneration in polyneuropathies?   Ann. Neurol.,
5: 501.

STAHL, W.R.  (1967)  Scaling of respiratory variables in
mammals.  J. appl. Physiol., 22: 453-460.

STERMAN, A.B.  (1982)  Acrylamide induces early morphologic
reorganization of the neuronal cell body.  Neurology, 32(9):

STERMAN, A.B.  (1983)  Altered sensory ganglia in acrylamide
neuropathy. Quantitative evidence of neuronal reorganization.
 J. Neuropathol. exp. Neurol., 42(2): 166-176.

STERMAN, A.B., PANASCI, D.J., & PERSONS, W.  (1983a)  Does
pyruvate prevent acrylamide neurotoxicity? Implications for
disease pathogenesis.  Exp. Neurol., 82: 148-158.

Autonomic-cardiovascular dysfunction accompanies sensory-
motor impairment during acrylamide intoxication.
 Neurotoxicology, 4: 45-52.

SUMNER, A.J. & ASBURY, A.K.  (1974)  Acrylamide neuropathy:
Selective vulnerability of sensory fibres.  Arch. Neurol., 32:

SUZUKI, K. & PFAFF, L.D.  (1973)  Acrylamide neuropathy in
rats. An electron microscopic study of degeneration and
regeneration.  Acta neuropathol., 24: 197-213.

SUZUKI, H. & SUZUMURA, M.  (1977)  [Determination of a small
amount of acrylamide in air.]  Sangyo Igaku, 19: 189-193 (in

TAKAHASHI, M., OHARA, T., HASHIMOTO, K.  (1971)  Electro-
physiological study of nerve injuries in workers handling
acrylamide.  Int. Arch. Arbeitsmed., 28: 1-11.

TANII, H. & HASHIMOTO, K.  (1981)  Studies on  in vitro
metabolism of acrylamide and related compounds.  Arch.
 Toxicol., 48: 157-166.

TANII, H. & HASHIMOTO, K.  (1982)  Structure-toxicity
relationship of acrylates and methacrylates.  Toxicol. Lett.,
11: 125-129.

TEAL, J.J. & EVANS, H.L.  (1982)  Behavioral effects of
acrylamide in the mouse.  Toxicol. appl. Pharmacol., 63:

& HESS, R.  (1974)  The assessment of peripheral neurotoxicity
in dogs: Comparative studies with acrylamide and clioquinol.
 Agent Actions, 4(1): 47-53.

TILSON, H.A.  (1981)  The neurotoxicity of acrylamide: an
overview. Neurobehav.  Toxicol. Teratol., 3: 113-120.

TILSON, H.A. & CABE, P.A.  (1979)  The effects of acrylamide
given acutely or in repeated doses on fore- and hindlimb
function of rats.  Toxicol. appl. Pharmacol., 47: 253-260.

TILSON, H.A. & SQUIBB, R.E.  (1982)  The effects of acrylamide
on the behavioural suppression produced by psychoactive
agents.  Neurotoxicology, 3: 113-120.

TILSON, H.A., CABE, P.A., & SPENCER, P.S.  (1979)  Acrylamide
neurotoxicity in rats: A correlated neurobehavioural and
pathological study.  Neurotoxicology, 1: 89-104.

TILSON, H.A., CABE, P.A., & BURNE, T.A.  (1980)  Behavioural
procedures for the assessment of neurotoxicity. In: Spencer,
P.S. & Schaumburg, H.H., ed.  Experimental and clinical
 neurotoxicology, Baltimore, Maryland, Williams and Wilkins,
pp. 758-766.

(1961)   N-N' -alkylene-bis (acrylamides),  N -(acrylamidomethyl-
3-halopropionamides and related compounds: A new series of
anti-tumour agents.  Nature (Lond.), 191: 611-612.

BLUNT, H.W.  (1967)  Synthesis of possible cancer
chemotherapeutic agents based on enzyme rationale. VI.
Allylamine derivatives.  J. pharm. Sci., 56(4): 484-488.

TURNER, C.J.  (1981)  Toxin-induced inhibition of nerve
terminal growth.  Neurotoxicology, 2: 313-327.

statement of the committee on new chemicals for water
treatment.  Water Treat. Exam., 18: 90.

UPHOUSE, L.L.  (1981)  Interactions between handling and
acrylamide on the striatal dopamine receptor.  Brain Res., 221:

UPHOUSE, L.L. & RUSSELL, M.  (1981)  Rapid effects of
acrylamide on spiroperidol and serotonin binding in neural
tissue.  Neurobehav. Toxicol. Teratol., 3: 281-284.

BONDY, S.C.  (1982)  Interactions between "handling" and
acrylamide on endocrine responses in rats.  Neurotoxicology, 3:

US EPA  (1978)   Environmental monitoring near industrial
 sites: Acrylamide, Washington DC, US Environmental Protection
Agency (EPA Report No. 560/6-78-001, PB-281 879).

US EPA  (1980a)   Assessment of testing needs - acrylamide,
Washington DC, US Environmental Protection Agency (EPA Report
No. 560/11-80-016, PB 80-220312).

US EPA  (1980b)   A foetal toxicity study of acrylamide in
 rats, Washington DC, US Environmental Protection Agency,
Information Control Branch (FYI-OTS-0680-0076).

US EPA  (1980c)   Acrylamide test rule, Washington DC, US
Environmental Protection Agency, Health Review Division
(TS-792), In-house memorandum, 10 March 1980.

US EPA  (1981)   Level 1 economic evaluation: Acrylamide,
Washington DC, US Environmental Protection Agency, Office of
Pesticides and Toxic Substances, 27 pp (Contract No.

US EPA  (1982a)   Communication with Dr R.W. Mast, Test Rules
 Development Branch, Washington DC, US Environmental Protection
Agency, Information Control Branch, Freedom of Information Act

US EPA  (1982b)   Acrylamide monomer: A two-year chronic
 toxicity-oncogenicity study administered via the drinking
 water fo CDF Fischer-344 rats, Washington DC, US Environmental
Protection Agency, Information Control Branch

US EPA  (1982c)   Chronic toxicity-oncogenicity study on
 acrylamide in Fischer 344 rats, Washington DC, US
Environmental Protection Agency, Information Control Branch

US EPA  (1983)  Acrylamide response to the Interagency Testing
Committee.  Fed. Reg., 48: 4.

USSR, MINISTRY OF HEALTH  (1979)   Maximum allowable
 concentrations of harmful substances in the air of the working
 zone 1972-79, Moscow, Ministry of Health of the USSR (List
No. 13).

VASAVADA, H.A. & PADAYATTI, J.D.  (1981)  Rapid transfection
assay for screening mutagens and carcinogens.  Mutat. Res., 91:

VIDYASAGAR, T.R.  (1981)  Optic nerve components may not be
equally susceptible to damage by acrylamide.  Brain Res., 224:

VON BURG, R., PENNEY, D.P., & CONROY, P.J.  (1981)  Acrylamide
neurotoxicity in the mouse: a behavioural, electrophysio-
logical, and morphological study.  J. appl. Toxicol., 1(4):

WALDEN, R. & SCHILLER, C.M.  (1981)  Quantitative analysis of
acrylamide in the milk of lactating rats following oral in
vivo exposure.  Environ. Toxicol., II: 678.

WALDEN, R., SQUIBB, R.E., & SCHILLER, C.M.  (1981)  Effects of
prenatal and lactational exposure to acrylamide on the
development of intestinal enzymes in the rat.  Toxicol. appl.
 Pharmacol., 58: 363-369.

(1976)   The merck index, 9th ed., Rahway, New Jersey, Merck &
Co., p. 127.

(1979)  Toxicodynamics of acrylamide in rats.  Toxicol. appl.
 Pharmacol., 48(1): 91.

    See Also:
       Toxicological Abbreviations
       Acrylamide (HSG 45, 1991)
       Acrylamide (ICSC)
       Acrylamide (WHO Food Additives Series 55)
       ACRYLAMIDE (JECFA Evaluation)
       Acrylamide (PIM 652)
       Acrylamide (IARC Summary & Evaluation, Volume 60, 1994)