Acrylamide neuropathy

Michael T Pulley MD PhD

Peripheral Neuropathies

Updated 04.01.2024
Released 12.03.1999
Expires For CME 04.01.2027

Acrylamide neuropathy

Author: Michael T Pulley MD PhD

See Contributor Disclosures

Editor: Louis H Weimer MD

Acrylamide neuropathy

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Introduction

Overview

The authors discuss the clinical manifestations of acrylamide neuropathy. This toxic neuropathy has served as a model for studying the effects of toxins on the nervous system. New information has emerged regarding the potential mechanism of the neuropathy. This may completely change the approach to research of toxic neuropathies.

Key points

	• Acrylamide causes a central-peripheral distal axonopathy.
	• The neuropathy in animals is predictable and has been used as a model for other forms of central peripheral distal axonopathy.
	• As with many toxic neuropathies, the manifestations are dose dependent, and the prognosis is dependent on the degree of central axonal degeneration.

Historical note and terminology

The neurotoxic effects of acrylamide have been known for over 50 years (15; 10). Acrylamide is used in grouting agents for soil and sealing applications (13), and polyacrylamide is used in flocculating wastewater treatment plants (09). The monomer is the toxic form, whereas the polymer is innocuous. However, the polymer may be contaminated by up to 2% monomer and can, thus, be a source of toxicity. Acrylamide is readily absorbed by inhalation, ingestion, or dermal contact. Acrylamide neuropathy has been a popular experimental animal model for studying the processes of axonal transport (19; 12), dying-back neuropathy (22), and axonal swelling. Studies have raised doubts about the basic underlying mechanism of acrylamide neuropathy (18).

Clinical manifestations

Presentation and course

The manifestations of acrylamide toxicity depend on the degree and duration of exposure. The usual route of exposure is through the skin; therefore, a contact dermatitis is usually present prior to the clinical symptoms of neuropathy. In the setting of acute exposure, malaise, dizziness, anorexia, and headache are often present. With high-level acute exposure, the neurologic picture includes encephalopathy with seizures and truncal ataxia followed by peripheral neuropathy (04). Early behavioral changes may be more or less apparent to the patient than others. With more chronic, low-level exposure, the dermatitis persists, but the CNS effects are not as prominent.

The neuropathy resulting from acrylamide is an example of a central-peripheral distal axonopathy. This describes a process whereby the distal portion of the longest peripheral axons are affected first, but with continued exposure, the distal segments of corticospinal, spinocerebellar, and dorsal column axons become subsequently involved (23). Early clinical manifestations include toe numbness and widespread hyporeflexia. Large fiber sensory dysfunction with loss of vibration and proprioception is common, whereas pain and paresthesias are rare (22). Acute, high-level exposure often results in widespread autonomic dysfunction such as impairment of reflex changes in heart rate and blood pressure, vasomotor changes in fingers and toes, and excessive sweating. Overt autonomic dysfunction is less common in chronic exposure and may be limited to excessive sweating of the hands and feet. Although sensory complaints dominate, motor and cerebellar deficits may be evident on physical examination. Cranial nerve function is unaffected.

Prognosis and complications

Removal from exposure usually results in recovery if the neuropathy is mild. Some residual loss of vibratory sensation may be apparent. However, in the case of severe neuropathy, spasticity, and ataxia, more profound sensory dysfunction and memory problems may remain. Central nervous system dysfunction, such as spasticity and upper motor neuron weakness, may be obscured initially by the peripheral nerve dysfunction. As nerve recovery ensues, clinical dysfunction may remain due to unresolved central nervous system dysfunction. Coasting, the worsening of symptoms after termination of exposure, may occur (05).

Biological basis

Etiology and pathogenesis

Acrylamide is absorbed by inhalation, dermal contact, or ingestion. Most occupational intoxication occurs through the dermal route. Both the parent compound and its metabolite, glycinamide, are neurotoxic (01). Acrylamide appears to selectively accumulate in the distal portions of peripheral nerves (02). A decrease in the activity of glutathione-S-transferase activity may be related to the onset of neuropathy (07). Acrylamide alters the profile of cytoskeletal proteins in the sciatic nerves of rats and this may be related to the mechanism of neuropathy (27).

Cell biology. Acrylamide appears to interfere with axonal transport (19; 12), resulting in an accumulation of neurofilaments and axonal swelling (21). The swelling is most prominent in the paranodal region, possibly due to the constriction of the axon at that point (24). The reduction in fast axonal transport is not dependent on neurofilaments, as transgenic mice without axonal neurofilaments also have reduction in fast axonal transport when exposed to acrylamide (25). In addition to the effects on axonal transport, high-level acute exposure has been shown in animals to cause chromatolysis in the dorsal root ganglion cells (26). Morphologic studies using silver stain have shown that the dose and acuity of exposure determine whether the damage is primarily at the nerve terminal or there is involvement of axons (16). The same group of investigators has subsequently extended this observation (17). They found that with 2 separate dosing regimens, nerve terminal damage was the initial manifestation of acrylamide toxicity. These researchers now question the significance of axonal swelling and feel it is a secondary event and not the primary mechanism of neuronal dysfunction. Studies of acrylamide neuropathy in rats have shown a correlation between neurophysiologic changes and altered levels of glutathione (reduced) and malondialdehyde (increased), suggesting oxidative stress may play a role in the mechanism of disease (28). Finally, although small fiber dysfunction is not a primary manifestation clinically, skin biopsy studies in mice show early changes in intraepidermal nerve fibers (14).

References

01: Abou-Donia MB, Ibrahim SM, Corcoran JJ, et al. Neurotoxicity of glycinamide, an acrylamide metabolite. J Toxicol Environ Health 1993;39:447-64. PMID 8345532
02: Ando K, Hashimoto K. Accumulation of (14-C)-acrylamide in mouse nerve tissue. Proc Osaka Perfectural Inst Pub Health 1972;10:7-12.
03: Barber DS, Hunt J, Lo Pachin RM, Ehrich M. Determination of acrylamide and gylcidamide in rat plasma by reversed-phase high performance liquid chromatography. J Chromatogr B Biomed Sci Appl 2001;758:289-93. PMID 11486839
04: Berger AR, Schaumburg HH. Effects of occupational and environmental agents on the nervous system. In: Bradley WG, Daroff RB, Fenichel GM, Marsden CD, editors. Neurology in clinical practice. Butterworth Heinemann, 1996.
05: Berger AR, Schaumburg HH, Schroeder C, Apfel S, Reynolds R. Dose response, coasting, and differential fiber vulnerability in human toxic neuropathy: prospective study of pyridoxine neurotoxicity. Neurology 1992;42:1367-70. PMID 1620347
06: Cavanaugh JB. The significance of the "dying-back" process in experimental and human neurological disease. Int Rev Exp Pathol 1964;3:219-67.
07: Dixit R, Mukhtar H, Seth PK, Murti CR. Conjugation of acrylamide with glutathione catalyzed by glutathione-S-transferase in rat liver and brain. Biochem Pharmacol 1981;30:1739-40. PMID 7271861
08: Duarte-Salles T, von Stedingk H, Granum B, et al. Dietary acrylamide intake during pregnancy and fetal growth-results from the Norwegian mother and child cohort study (MoBa). Environ Health Perspect 2013;121:374-9. PMID 23204292
09: Feldman RG. Acrylamide. In: Occupational and environmental toxicology. Philadelphia: Lippincott-Raven Publishers, 1999;337-58.
10: Fujita A, Shibata J, Kato H, et al. Clinical observations of three cases of acrylamide poisoning. Nippon Ijo Shimpo 1960;1869:37-40.
11: Fullerton PM. Electrophysiologic and histologic observations on the peripheral nerves in acrylamide poisoning in man. J Neurol Neurosurg Psychiatry 1969;32:186-92. PMID 4307538
12: Gold BG, Griffin JW, Price DL. Slow axonal transport in acrylamide neuropathy: different abnormalities produced by single-dose and continuous administration. J Neurosci 1985;5:1755-68. PMID 2410575
13: Kjuus H, Goffeng LO, Heier MS, et al. Effects on the peripheral nervous system of tunnel workers exposed to acrylamide and N-methylolacrylamide. Scand J Work Environ Health 2004;30(1):21-9. PMID 15018025
14: Ko MH, Chen WP, Hsieh ST. Neuropathology of skin denervation in acrylamide-induced neuropathy. Neurobiol Dis 2002;11:155-65. PMID 12460555
15: Kuperman AS. Effects of acrylamide on the central nervous system of the cat. J Pharmacol Exp Ther 1958;123:180-92. PMID 13564393
16: Lehning EJ, Balaban CD, Ross JF, LoPachi RM. Acrylamide neuropathy. II. Spatiotemporal characteristics of nerve cell damage in brainstem and spinal cord. Neurotoxicology 2003;24:109-23. PMID 12564387
17: LoPachin RM, Balaban CD, Ross JF. Acrylamide axonopathy revisited. Toxicol Appl Pharmacol 2003;188(3):135-53. PMID 12729714
18: LoPachin RM, Gavin T. Toxic neuropathies: mechanistic insights based on a chemical perspective. Neurosci Lett 2015;596:78-83. PMID 25218479
19: Miller MS, Spencer PS. Single doses of acrylamide reduce retrograde transport velocity. J Neurochem 1984;43:1401-8. PMID 6208333
20: Park RM. Preliminary risk assessment for acrylamide and peripheral neuropathy. Neurotoxicology 2021;85:10-7. PMID 33892018
21: Schaumburg HH, Arezzo JC, Spencer PS. Delayed onset of axonal neuropathy in primates after prolonged low-level administration of a neurotoxin. Ann Neurol 1989;26:576-9. PMID 2817831
22: Schaumburg HH, Wisniewski HM, Spencer PS. Ultrastructural studies of the dying-back process. I. Peripheral nerve terminal and axon degeneration in systemic acrylamide intoxication. J Neuropathol Exp Neurol 1974;33:260-84. PMID 4362700
23: Spencer PS, Schaumburg HH. Central-peripheral distal axonopathy-the pathogenesis of dying back polyneuropathies. In: Zimmerman H, editor. Progress in neuropathology. Vol 3. New York: Grune and Stratton, 1976:253-95.
24: Spencer PS, Schaumburg HH. Ultrastructural studies of the dying back process. III. The evolution of experimental peripheral giant axonal degeneration. J Neuropathol Exp Neurol 1977;36:276-99. PMID 190357
25: Stone JD, Peterson AP, Eyer J, Sickles DW. Neurofilaments are non-essential elements of toxicant-induced reductions in fast axonal transport: pulse labeling in CNS neurons. Neurotoxicology 2000;21:447-57. PMID 11022855
26: Tandrup T. Chromatolysis of A-cells of dorsal root ganglia is a primary structural event in acute acrylamide intoxication. J Neurocytol 2002;31:73-8. PMID 12652089
27: Yu S, Son F, Yu J, et al. Acrylamide alters cytoskeletal protein level in rat sciatic nerves. Neurochem Res 2006;31(10):1197-204. PMID 17043767
28: Zhu YJ, Zeng T, Zhu YB, et al. Effects of acrylamide on the nervous tissue antioxidant system and sciatic nerve electrophysiology in the rat. Neurochem Res 2008;33:2310-7. PMID 18470611

Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Author

Michael T Pulley MD PhD

Dr. Pulley of the University of Florida, Jacksonville received consulting fees from Argenx, Alexion, and UCB/Ra.
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Editor

Louis H Weimer MD

Dr. Weimer of Columbia University has no relevant financial relationships to disclose.
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Former Authors

Alan R Berger MD

Patient Profile

Age range of presentation: 19 to 64 years
Sex preponderance: male=female
Heredity: none
Population groups selectively affected: none selectively affected
Occupation groups selectively affected: manufacturing plant workers

ICD & OMIM codes

ICD-9: Polyneuropathy (peripheral) caused by accidental poisoning by corrosives and caustics not elsewhere classified: 357.7, E864.2
ICD-10: Polyneuropathy due to other toxic agents: G62.2

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Acrylamide neuropathy

Associated Disorders

Dermatitis
Encephalopathy

Differential Diagnosis

distal axonopathy

Also Relevant

Chronic autonomic neuropathies
Introduction to and clinical evaluation of peripheral neuropathies
Introduction to toxic peripheral neuropathies

Clinical Categories

Peripheral Neuropathies

Acrylamide neuropathy

Acrylamide neuropathy

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Diagnostic workup

Management

Special considerations

Pregnancy

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview.
Start a Free Account
to access the full version.

Questions or Comment?

Also in This Category

Neuropathies associated with cytomegalovirus infection

Clinical evaluation of peripheral neuropathies

Hypothyroidism

Monoclonal gammopathy of neurologic significance

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Amyotrophic lateral sclerosis

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Autoimmune autonomic neuropathy

Acrylamide neuropathy

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Diagnostic workup

Management

Special considerations

Pregnancy

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Neuropathies associated with cytomegalovirus infection

Clinical evaluation of peripheral neuropathies

Hypothyroidism

Monoclonal gammopathy of neurologic significance

Chronic inflammatory demyelinating polyradiculoneuropathy

Amyotrophic lateral sclerosis

Amiodarone neuropathy

Autoimmune autonomic neuropathy

This is an article preview.
Start a Free Account
to access the full version.