Prevalence of acrylamide in foodstuffs

Published: Last Edited:

This essay has been submitted by a student. This is not an example of the work written by our professional essay writers.


This review of the current literature aims to examine the evidence base for the safety of acrylamide in humans. It will do this by considering various aspects of acrylamide, such as its chemistry, its metabolic fate in the body, and the body of research which is currently available relating to its toxicity, both as a neurotoxin and as a mutagen. It has to be noted that the majority of work in this area has been done on rodents and therefore this review will also examine the applicability of the rodent-derived data for the human model.

This review also sets out the background to acrylamide, to enable the reader to understand how it is formed and how it arrives in the human food chain. It then presents the evidence base for its classification as a 'probable carcinogen' and the evidence base for its role as a neurotoxin.

It also set out to determine what actual levels that humans are generally exposed to as well as to ascertain whether there is considered to be a safe upper limit of ingestion and whether this concurs with the current legislative restrictions on acrylamide.

Various foods that have high levels of acrylamide are detailed together with the most authoritative estimates of its potential for genotoxicity. This is presented at length in the discussion and conclusion section but, in essence, it has to be concluded that although the evidence base for acrylamide being considered a neurotoxin is strong, the evidence base relating to its mutagenicity is both contradictory and weak.


Acrylamide, a versatile organic compound, (Semih - 2007) has been known to chemists, especially food chemists, for nearly a century. It has multiple industrial uses and is a product of the cooking process in many foods which contain reducing sugars. It is known to have neurotoxic properties and more recently, there has been evidence to suggest that it may be mutagenic. There was widespread public concern in the late 1990s when the authorities in Sweden discovered alarmingly high levels of acrylamide in food consumed by some elements of the population. This resulted in an enquiry and a flurry of work on the toxic potential of acrylamide.

Acrylamide and its chemical structure

Acrylamide is a monomeric chemical which is commercially used in the synthesis of Polyacrylamide. The single unit form of acrylamide is toxic to the nervous system, a carcinogen in laboratory animals, and a suspected carcinogen in humans. The polymeric form is unknown to be toxic (Giese, 2002; Konings et al., 2003; Richmond and Borrow, 2003; Tyl and Crump, 2002; Vattem and Shetty, 2003).

Acrylamide is normally found in a white crystalline form. Its physical properties are that it is an odourless and tasteless solid. It is known to dissolve in a number of solvents including water, ethanol, methanol, dimethyl ether and acetone. Unlike many similar chemicals it is soluble in neither haptane nor benzene.

When acetylamide reaches its meting point it polymerises and this is also the case when it is exposed to UV light. It is physically stable at room temperature but has the ability to polymerise violently when rapidly melted or allowed to come into contact with oxidising agents. (Barone &,Giancola 2005)

Its synonyms include 2-Propenamide, ethylene carboxamide, acrylic amide, vinyl amide and it has a molecular weight of 71.09. The chemical formula is CH2CHCONH2 . It has a boiling point of 125°C and a melting point of 87.5°C.

Carcinogenic effects of acrylamide

Acrylamide is currently classified as a Group 2A carcinogen by the International Agency for Research on Cancer and a Category 2 carcinogen and Category 2 mutagen by the European Union (IARC 1994).

  • Acrylamide is present is the environment is varying quantities. When in the body, it is metabolised by oxidation and its prime metabolite, glycidamide is known to be mutagenic (Adler, I. D et al., 2000). Glycidamide is a reactive epoxide, and undergoes conjugation with glutathione. (Sumner, S. C et al., 1992).
  • It is also believed that acrylamide can be generated from particular food components when they are being heat treated (the Maillard reaction) as the result of a reaction between asparagine (an amino acid) and reducing sugars.
  • The majority of experimental work on this substance has been done in rodents. One should note that in the rat model, the rate of elimination of acrylamide is at least five times lower in man than in the rat. The intuitive corollary of this finding is that, within broad parameters, the experimental findings of carcinogenesis in the rat model are therefore likely to understate the situation in the human. (Calleman, C. J. 1996).

    Although direct extrapolation to humans from the rat model is clearly not possible, one should note that extensive testing of the rat model has shown that acrylamide is carcinogenic when given to rats over a two year period in their drinking water. These rats showed statistically significant increases in the incidence of several tumour types (mainly testicular mesotheliomas and mammary gland adenomas) in animals of both sexes when they were compared to the control animals (Friedman, M. A et al., 1995)

    To cite the conclusions of the Dybing study almost verbatim:

    Using the conservative default linear extrapolation methods LED10 and T25 for genotoxic carcinogens..... the lifetime cancer hazard after lifelong exposure to 1 µg acrylamide per kg body weight per day scaled to humans was, on average, calculated to be 1.3 x 10-3. Using this hazard level and correlating it with the exposure estimates, a lifetime cancer risk related to daily intake of acrylamide in foods for 70 years in males was calculated to 0.6 x 10-3....... corresponding to 6 cancer cases per 10,000 individuals. For the 10% and 2.5% males with the highest intakes...... lifetime cancer risks were estimated to 13 and 21 cancer cases per 10,000 individuals. For females, the risk values were slightly lower. (Dybing E F et al., 2003) )

    Besaratinia et al., have confirmed the mutagenicity of acrylamide at low concentrations in different mammalian cell lines in a series of evidence level Ib studies. (Besaratinia, A et al., 2004) and Rice has suggested that, based on conventional risk assessment calculations of the limited data currently available from two major rodent studies, the additional cancer risk in the population is estimated to result from a daily lifetime uptake of 70 µg acrylamide with the food was in the order of magnitude of 1 - 10-3 (Rice J M 2005). Clearly such extrapolations must be generalised with great caution as the very few epidemiological studies on human populations (viz. Mucci L A et al., 2004 & 2005) have failed to confirm any significant increased cancer risk caused by acrylamide intake with food, but these studies have significant methodological limitations.

    Acrylamide has long been recognised as a potent neurotoxin. (LoPachin R M 2004) work in the last decade has also revealed that it has marked properties of germ cell mutagenesis. In rodent models it has been shown to be associated with generation of tumours at multiple organ sites including follicular thyroid tumours, adrenal pheochromocytomas, scrotal mesotheliomas, mammary gland tumours, lung adenomas and carcinomas, glial brain tumours, oral cavity papillomas, and uterine adenocarcinomas (Rice J M. 2005).

    As has been discussed elsewhere, the evidence base for the induction of a neoplastic process in humans is poor, mainly because it is extremely difficult to correlate any dietary consumption of acrylamide with a specific cancer outcome. Moreover, the few occupational studies that have been published have failed to show that acrylamide is carcinogenic to industrial workers, possibly due to the apparently long lead time before malignancies develop in the human model. It is therefore extremely important to study the mechanisms of action of acrylamide in order to understand how this genotoxicant may affect the human genome.

    The actual mechanism of mutagenesis is believed to be primarily by the induction of breakages in the chromatin material with Ghanayem et al. pointing out that this effect is twice as common in cells exposed to glycidamide than in ones exposed to acrylamide, the effect being dose dependent. (Ghanayem B I et al., 2005)

    In summary, it would appear that, in the biological setting it is the binding of acrylamide to plasma proteins together with its conjugation with glutathione which effectively compete against the effects of acrylamide genotoxicity, which arises from the reaction of this compound or its metabolite, glycidamide, with DNA (Friedman M. 2003). When acrylamide is conjugated with glutathione it effectively depletes the glutathione stores within the cells and thereby changes the redox status of the cell. This can potentially affect gene expression directly or through regulating various transcription factors, which are redox dependent (Tsuda H et al., 2003). This observation has led some researchers to suggest that acrylamide may exert its effects independently of a direct acrylamide effect on the DNA. Others have also suggested a hormonal mode of action based on the observation of acrylamide on tumour formation in endocrine (thyroid) and mammary gland tissue, but the evidence base is far more tenuous in this area. (Bolt H M. 2003).

    Other harmful effects to the body

    If one considers the pharmokinetics of acrylamide, then one must note that the majority of the work published has been in rodents. The majority of studies done have shown qualitative similarities across the mammalian species, so a degree of confidence in the generalisability of results appears justified. (Dybing et al., 2005).

    Friedman suggests that it is the low molecular weight and high water solubility of acrylamide that enable this compound to easily pass through various biological membranes (Friedman M. 2003). It is this fact combined with its characteristic chemical structure as well as its ability to undergo metabolic transformation which make it react with different targets at the sub cellular level. (Sumner S C et al., 1999)

    It is known that acrylamide is rapidly absorbed from the gut in humans as well as being able to cross both the blood/placenta barrier in a human placenta in an in vitro model as well as crossing the blood/breast milk barrier in vivo of lactating mothers. (Sörgel F et al., 2002). It therefore seems reasonable to assume that ingested acrylamide is able to reach any human tissue.

    A proportion of the acrylamide is metabolised to form an epoxy derivative, glycidamide by the enzyme, CYP2E1, which is part of the cytochrome P450 pathway. (Sumner S C et al., 1999). Both acrylamide and its metabolite glycidamide can bind covalently to nucleophilic sites of biological macromolecules.

    Doerge reports that these are predominantly the -SH and -NH2 groups of proteins and nucleic acid nitrogens. (Doerge D R et al., 2005)

    For this reason, Dybling et al. point out that both acrylamide and glycidamide adducts to the NH2-terminal valine of human haemoglobin are commonly used as convenient biomarkers for acrylamide and / or glycidamide exposure Further metabolism results in conversion to mercapturic acid metabolites which results in the finding of N-acetyl-S-(2-carbamoylethyl) cysteine (AAMA) and N-acetyl-S-(2-hydroxy-2-carbamoylethyl) cysteine (GAMA) in the urine which can also be considered as a convenient biomarker. (Dybling E et al., 2005).

    The detection of the urinary markers suggests a significant difference between rodents and humans as, in humans the predominant metabolite excreted is AAMA which suggests that detoxification, together with elimination of unchanged acrylamide, is more efficient than formation of the more reactive epoxy metabolite glycidamide. This is distinctly different to the rodent model where excretion of the glycidamide-derived metabolite, GAMA, is at least twice as high in rats and 4 times as high in mice, which suggests that extrapolations of the cancer risk in humans determined from rodent experiments would need to be corrected by at least a similar factor. (Fuhr U et al., 2006)

    The prime non-mutagenetic activity of acrylamide in the human body is as a neurotoxin exerting an effect on both the central and peripheral nervous systems. It is also known to be a skin and airway irritant with degrees of absorption into the body by both these routes.

    Given the fact that there appears to be some evidence that acrylamide ingestion is associated with mutagenesis, this begs the question of whether there is a minimum safe dose. Many studies with carcinogens have found that the body's natural immune defence mechanisms can identify neoplastic change in cells and invoke a number of cellular protective mechanisms when the levels of mutagenesis is comparatively low. These mechanisms can include intracellular detoxication processes, cell cycle arrest, DNA repair, apoptosis and the control of neoplastically transformed cells by the immune system. (Abramsson-Zetterberg, L. 2003).

    The maximum safe dose is often described as the NOAEL dose (no-observed-adverse-effect level). Perhaps the best estimate of this dose is offered by the evidence level Ib Swaen et al. study which estimated the NOAEL dose of acrylamide in humans as 0.1 mg/kg bw/day, although it should be noted that there was a non-significant increase in testicular mesotheliomas at this dose in one of the two experiments. (Swaen G M H et al., 2007)

    Uses of Acrylamide

    Acrylamide is an important chemical in industrial applications that has been produced for about 50 years in Europe and the rest of the industrialised world. Acrylamide has a huge number of potential applications and, as such it can be found in a number of different processes. It is used as starting material for the synthesis of polyacrylamide polymers, which are used in various aspects of drinking and waste water treatment, as a grouting agent, as a soil stabilizer, in the pulp and paper processing industries as well as in mining and mineral processing. Acrylamide can also be found as an ingredient in several cosmetic formulations. (Manière I et al., 2005)

    Until the late 1990s, acrylamide was mainly regarded as an industrial or occupational hazard, and the primary routes of exposure were thought to be absorption through the skin and inhalation of aerosols in industrial settings. In 1997, testing in response to an unexplained observation of a neurotoxic outbreak in Sweden uncovered high amounts of acrylamide in foodstuffs which triggered renewed interest and investigation into the possibility of the genotoxicity of the substance. (LoPachin R M 2004).

    Polyacrylamide and its practical importance

    Polyacrylamide is the polymerised form of acrylamide. It has a number of practical applications. It is used in industrial applications such as secondary oil recovery, as a thickening agent, a flocculant, and an absorbent, and to separate macromolecules of different molecular weights, most notably in gel electrophoresis which therefore means that it has an important place in a huge number of researches, industrial and medical applications.

    In the context of pharmaceuticals, there is a major problem in maintaining stability of various proteins that are used as therapeutic agents. Under normal physiological conditions a therapeutic protein is likely to denature, form aggregates and precipitates, and then eventually degrade. Polyacrylamide is often used as a pre-treatment to prevent this happening. (Zhang L et al., 2008)

    Acrylamide in Foodstuffs

    Acrylamide is a substance also found in human foodstuffs, most commonly in fried and baked starch-enriched food which has been prepared at temperatures in excess of 120°C (Tareke E et al., 2002). It arises mainly as a result of the interaction of asparagine, an amino acid, with reducing sugars (Stadler R H et al., 2002). The actual composition, preparation and cooking conditions markedly effect the degree of acrylamide formation and it has been calculated by in the evidence level III paper by Dybing et al. that the average daily intake of acrylamide for adults in western countries is likely to be in the range of 0.2 to 1.4 µg/kg body weight, with 0.5 µg/kg body weight probably as the best guess. The same authors also point out that younger age groups, on typically different diets, can achieve a higher intake with some sources reporting reaching up to 3.4 µg/kg body weight daily (95th percentile) in a Berlin cohort (Dybing E et al., 2005)

    The biological half-life of free acrylamide in humans is estimated at ~4.6 h (Calleman, C J 1996)

    Acrylamide is currently classified as a known carcinogen and the rating is largely based on rat studies and it is described as 'probably carcinogenic' in humans (IARC 1994).

    References to actual levels in foodstuffs

    The World Health Organization currently estimates a daily intake of dietary acrylamide in the range of 0.3-2.0 µg/kg/body wt for the general population of adults. Clearly this is an average under a Gaussian curve. Those who are at the upper end of this distribution above the 90th centile for acrylamide ingestion will be in the range of 0.6-3.5 µg/kg/body wt, and as high as 5.1 µg/kg/body wt for the 99th-percentile consumers. In children, the intake is estimated to be considerably higher, perhaps 2 - 3 times higher, partly because of a typically different food intake pattern but also because of different body morphology. If the whole population is considered, then the daily intakes of dietary acrylamide are estimated to be on average between 1 and 4 µg/kg/body wt.

    This is primarily obtained from dietary sources and the WHO calculates the breakdown thus: potato chips (16-30%), potato crisps (6-46%), coffee (13-39%), pastry and sweet biscuits (10-20%) and bread and rolls/toasts (10-30%). Other food products can account for <10% of the total intake of dietary acrylamide. (WHO 2005)

    Quantitative tests on foodstuffs have shown that acrylamide concentration varies widely across different samples of similar types of food depending on the mechanism of preparation. (Thulesius O J et al., 2004)

    Fig 2. Fast-food French fries showed the highest levels of acrylamide among the foods CSPI had tested, with large orders containing 39 to 82 micrograms. One-ounce portions of Pringles potato crisps contained about 25 micrograms, with corn-based Fritos and Tostitos containing half that amount or less. Regular and Honey Nut Cheerios contained 6 or 7 micrograms of the carcinogenic substance. The amount of acrylamide in a large order of fast-food French fries is at least 300 times more than what the U.S. Environmental Protection Agency allows in a glass of water (Center for science in the public interest)

    As an illustrative example, one can note that potato chips range from 330 to 2300 micrograms (µg) per kg which is dependent, in part, upon the actual method of preparation with higher cooking temperatures being associated with higher levels of acrylamide concentration. To put these levels into perspective then one can note that the World Health Organization guidelines currently limit concentration in drinking water to 1 mg of acrylamide per litre of water and stricter European Union regulations currently set the limit at 0.1 mg per litre.

    The definitive levels of toxicity of acrylamide in humans is still a matter of considerable controversy with the evidence level III paper by Ghanayem et al. making the comment that there was great methodological difficulty in extrapolating experimental rodent data to humans. He also goes on to illustrate the point with the comment that differences in carcinogen sensitivity and metabolism limit the relevance of interspecies comparisons, but added that a person would have to eat 75 kg of chips per day to get even one-tenth of the lowest observed genotoxic dose in rats, which is thought to be 25 mg per kg. (Ghanayem B I et al., 2009)

    In order to offer a balanced argument in this issue, one must also consider studies which appear not to demonstrate a relationship between acrylamide and malignancy. If fact the evidence level IIb Sobel study actually found a negative correlation. This review has been at pains to point out that the link between acrylamide and malignancy is not straightforward.

    Although the study is now comparatively old (1986), it is largely methodologically sound. The study considered nearly 400 employees at a factory in the USA which manufactured acrylamide. They found that 29 deaths had occurred (that were traceable). There were 11 deaths due to some form of cancer, compared to the 7.9 that would be statistically expected. The cancers were primarily of the digestive tract and of the lungs in a subgroup that had previous exposure to organic dyes. Among the employees who had a degree of exposure to organic dyes, four deaths were observed compared to the 6.5 expected. (Sobel, W et al., 1986). Clearly there may be some bias in the tracing methods and equally it is possible that the bio-protection was so efficient that the workers were exposed to smaller amounts of carcinogens than expected although intuitively this is unlikely. It is equally possible that a greater proportion died of another cause. This was not reported as the researchers were primarily considering malignancies as a cause of death.

    For all of the reasons set out above, estimates of the actual risks offered by acrylamide ingestion are very hard to assess authoritatively. One of the most authoritative could be that offered by the evidence level III paper by Dybing & Sanner

    When the average intake doses are correlated to the best hazard estimates [risk = (lifetime hazard after lifelong exposure to 1 µg acrylamide per kg body weight per day) x dose], a lifetime cancer risk related to daily intake of acrylamide in foods for 70 years becomes, on average, 0.6 x 10-3, which effectively corresponds to 6 cancer cases per 10,000 individuals. For those individuals (male) who were at the highest end of the intake spectrum (top 10% and 2.5%) the lifetime cancer risks were estimated to 13 and 21 cancer cases per 10,000 individuals, respectively. For females, the lifetime cancer risks were somewhat lower than for males. (Hogervorst J G et al., 2008)

    Evidence level Ib studies that have considered the exposure of acrylamide in drinking water where rodents were given the dose of 0.46 µg per kg body weight per day which equates to the acrylamide intake found in the average Norwegian male (Sanner T O et al., 2001) over a two year period, have concluded that there is an increased risk of testicular mesotheliomas and mammary gland adenomas. (Tyl R W et al., 2000)

    The chemistry of the Maillard reactions

    The Maillard reactions are named after the French scientist Louis Camille Maillard (1878-1936) who studied the reactions of amino acids and carbohydrates in 1912, as part of his PhD thesis, which was published in 1913 (Maillard L C 1913)

    It is something of a misnomer as it is actually a class of reactions between amino acids and reducing sugars rather than one specific reaction and is characterised by non-enzymatic browning. The products are responsible for many of the 'tastes' that are found in cooked foods. In the context of this review, it should be noted that Maillard reactions are important in baking, frying or otherwise heating of nearly all foods. Maillard reactions are partly responsible for the much of the flavour of bread, cookies, beer, cakes, chocolate, popcorn, cooked rice and meat. In many cases, such as in coffee, the resultant flavour is a combination of the products of a Maillard reaction and caramelisation. However, caramelisation only takes place above 120-150 °C, whereas Maillard reactions already occur at room temperature.

    The first step of the Maillard reaction is the reaction of a reducing sugar, such as glucose, with an amino acid and results in a product called an Amadori compound. The larger the sugar molecule, the slower it will react with amino acids. The final result is a very complex mixture, including flavour compounds and brown high molecular weight pigments called melanoidins. The resultant reactions thereby change the colour and flavour of food, and in most cases these changes are considered to improve the food. It is also the case that some of the melanoidins may have some beneficial anti-oxidant properties. Equally the Maillard reaction can reduce the nutritional value of a product, as amino acids and carbohydrates may be lost.

    In specific consideration of the thrust of this review, it should be noted that some of the Maillard end-products may also be toxic or carcinogenic. Acrylamide, which is formed as a result of a Maillard reaction, is a compound which is only formed only at temperatures above 180 °C, especially in baked or fried products (French fries). When frying below 180 °C acrylamide is not formed. (Fennema O R 2006).

    Swedish experience 1997

    In 2002, the Swedish authorities announced that they had found unusually high levels of acrylamide in a variety of foodstuffs including certain fried, baked, and deep-fried foods, and, at a later date, in coffee. (SNFA 2002)

    The concerns were traced back to Oct 1997 when inhabitants of the Bjare peninsula in south-western Sweden began to report that their cows suddenly became paralysed and died, and dead fish were found floating in breeding pools. (Reynolds T 2002).

    Investigations were launched and it transpired that the cause was likely to be as a result of a massive railroad tunnel that was being bored through the Hallandsås horst, a ridge of very porous rock which lay between two faults in the earth's crust. The contractors for the tunnel had experienced great difficulty in trying to plug leaks that played havoc not only with tunnel construction, but with the water table in the region's rich farmland. It appears that the contractors used 1,400 tons of a sealant called Rhoca-Gil to inject and try to seal the cracks in the tunnel walls and this had succeeded in contaminating ground and surface water with the toxic chemical acrylamide. Tunnel workers suffered numbness due to neurotoxicity. (Granath, F A et al., 2003)

    The economic and health repercussions were extensive as fear of contamination of milk caused milk from the region was dumped, vegetables were left to rot in the fields, and cattle were slaughtered and burned. (Besaratinia, A B et al., 2007)

    No human deaths were reported to be directly attributable, but the potential for long term mutageneicity has been carefully studied.

    The significance of this event was not so much that there was a well investigated human mass exposure to acrylamide but, during the investigation, the researchers noted that there was a background level of acrylamide (in the form of a reaction product or adduct) bound to haemoglobin which was seen in people who were not exposed to acrylamide in an industrial setting. This suggested that there was possibly exposure in the form of foodstuffs. As has been reported elsewhere in this review, rodents fed on fried food had higher levels of the acrylamide adduct than those fed on boiled food which suggested that the method of food preparation may be relevant. (Granath F A et al., 2003)

    The same group then went on to determine that acrylamide was found at particularly high levels in fried and potato-based foods. Potato chips, French fries, biscuits, and crackers had the highest levels, while breads, breakfast cereals, and corn chips had somewhat lower amounts. Boiled foods and animal products (even when fried) had relatively negligible levels.( Besaratinia A et al., 2007)

    Initial studies suggested that the human exposure to acrylamide in this case was between the limits of 38 and 29 µg acrylamide per day in males and females, respectively, which correlate to intake doses of about 0.49 and 0.46 µg per kg body weight and day. The 97.5-percentiles of adults had intakes that were approximately 3-fold higher than the mean intakes.

    The Swedish authorities estimated that, of the various foods assayed, coffee was the single greatest contributor to the total mean intake of acrylamide at 28%, potato crisps were responsible for almost 20% of the total intake. Bread was found to have fairly low levels but because it is eaten in such large quantities it accounted for about 21 - 24% of the total exposure.

    These proportions were applicable to the adult population. The exposure for children was quite different with crisps and biscuits comprising about 55 - 65% of the total. The Dybing review notes that the 97.5-percentile of 13-year-old boys and girls have intakes that are about 4- to 5-fold higher than the mean intakes. (Dybing E et al., 2003)

    Current legislation

    At an international level, one can note that acrylamide has been classified as a Group 2A carcinogen by the International Agency for Research on Cancer

    The legislative controls for acrylamide have been reviewed over the years and this has resulted in extremely complex regulations. There is no merit in slavishly rehearsing all of these so, as an illustrative example, this review can note that in 1993 the World Health Organisation (WHO) guidelines, which controlled acrylamide levels in water intended for drinking and other domestic purposes as well as water used in food production, sets a guideline value of 0.5 mg/L for acrylamide. The same set of regulations also specified a long-term occupational maximum exposure limit of 0.3 mg/m3 for acrylamide which is duplicated in Schedule 1 of the UK COSSH regulations (The Control of Substances Hazardous to Health Regulations 1994).

    These levels were subsequently revised downwards in 1998 when the EC directive, which is applicable in the UK, sets a mandatory maximum limit of acrylamide in drinking water of 0.1 mg/L in the EC Directive on the Quality of Water Intended for Human Consumption (98/83/EC),

    The same directive sets an advisory maximum total intake of 140 micrograms a day for a 70kg (154lbs) male.

    Aim and objectives

    Aim of the review

    The aim of this systematic review is to present an overview of the evidence base supporting the elements relating to the health implications for ingested acrylamide.

    Objectives of the review

    1. To outline the historical position for the concerns about acrylamide.
    2. To offer an overview of the chemistry, uses and applications of acrylamide in modern use.
    3. To outline the chemistry behind the Maillard reactions.
    4. To consider the evidence that acrylamide is a carcinogen
    5. To consider the evidence that acrylamide has other toxic effects on the human body
    6. To consider the implications of the Swedish experience of 1997
    7. To determine what levels of acrylamide are actually found in food
    8. To consider the current legislative controls of acrylamide
    9. To consider if there is a 'safe' level of acrylamide.
    10. To arrive at a conclusion for all of the points above.

    Methodology of the literature review

    These aims were achieved by an extensive searching of the available database.

    Searching of these databases took place at Aston University reference library. In addition to these specialist databases, a number of other online databases were searched including Ovid, Medline, Cinhal, hi-wire, Questia, The Lancet, British Journal of Nursing, BMJ, and the Open University.

    The search terms use included:

    • Acrylamide
    • Maillard reaction
    • Toxin
    • Mutagen
    • Foodstuff
    • Cooking
    • Sweden
    • Glycidamide
    • Toxic dose
    • Half-life

    These were used in various combinations to sift the database. This allowed for relevant papers to be identified within the first five searches. There were virtually no new papers found in subsequent combinations. 142 papers were identified as relevant.

    A general exclusion policy was implemented for this review of papers which were more than ten years old unless there was a specific reason, such as either historical or landmark status, for their inclusion, or a more recent paper of equivalent evidential value could not be found.

    The preferred inclusion criteria were papers that were less than eight years old and which, after critical appraisal, made a substantial and appropriate contribution to the evidence base in this area.

    This process allowed for an assemblage of relevant papers and studies. Each paper was critically appraised and assigned an appropriate evidence level (see appendix). The most significant, recent paper with the highest evidence level was then put forward for inclusion in relation to each point.


    The issues relating to the mutagenic effects of acrylamide are both complex and as yet not universally resolved. On balance, there seems to be a large evidence base to suggest that acrylamide has the ability not only to act as a neurotoxin but also as a genotoxic agent. The debate appears to arise from the applicability of rodent-derived results to the human model. Clearly there is no ethical pathway to derive the results directly and therefore extrapolation appears to be the only way to obtain evidence other than by studies that examine accidental exposure. It is difficult to investigate the effects of acrylamide because the mutagenic effects occur long after exposure. The last major mass exposure was in Sweden only thirteen years ago and, although the situation is being monitored by the Swedish authorities, there are no studies published yet which detail the long term results.

    It is clear that acrylamide is produced in foods cooked at a high temperature with potato crisps and fried meats having particularly high levels. There is also a wide range of dietary exposure which largely depends on the cooking and eating patterns of the individuals involved. It would appear that children typically have considerably higher (proportional) doses than adults.

    The biological pathways of metabolism do appear to have been substantially evaluated with accurate biological markers of both ingestion and metabolism being identified. (Fennell, T R et al., 2005). It would appear that the evidence suggests that there is a lower 'safe' exposure level as the body appears to have a number of repair mechanisms at the cellular level which can deal with minor degrees of genetic damage including the intracellular detoxification processes, cell cycle arrest, DNA repair, apoptosis and the control of neoplastically-transformed cells by the immune system (Martins C G et al., 2007).

    The Swedish experience led to an explosion of research activity in this area with the literature showing evidence of renewed interest in the biological effects of acrylamide. It was largely responsible for the realisation that acrylamide exposure was a general phenomenon ingested from cooked foodstuffs by the general population rather than simply a problem of exposure to a comparatively few workers at industrial sites.

    The legislation controlling acrylamide has been updated several times in the last two decades and does vary across the developed world. The maximum permissible level of acrylamide in drinking water in the EEC is currently 0.1 mg/L because of the vagaries of cooking processes in the domestic situation it has not yet been possible to regulate against exposure in cooked foods. The current best estimates for average ingestion are in the region of 0.3-2.0 µg/kg/body wt of acrylamide for the general adult population.

    An intake of 1 µg acrylamide per kg body weight over an average lifetime is estimated to equate to 6 cancer cases per 10,000 individuals, but one has to accept that such estimates have a huge number of assumptions and extrapolations.

    In essence, there appears to be a substantial, but as yet incomplete, evidence base to support the view that acrylamide is certainly neurotoxic and probably mutagenic in the human model. The actual dose/effect relationship has not yet been reliably defined. It is believed that acrylamide exerts a mutagenic effect primarily by an action of its major metabolites directly on the cellular DNA by means of chromatin damage. Small amounts of that damage can be repaired or neutralised at a cellular level, but it is likely that larger amounts of damage can be manifest, after a substantial lag period, in a number of forms of malignancy, primarily of the digestive and reproductive organs, although some endocrine organs may also be affected.

    Future Work

    This review has demonstrated that the research behind the toxicity of acrylamide is still in working progress. Further work could therefore involve the reduction of acrylamide in food stuffs by tackling the reactions in which acrylamide are made. However it is important to remember that this can only be done once acrylamide is acknowledged as a dangerous chemical at high doses. Therefore, new research could be concentrated to find the effects of acrylamide moreover in humans rather than rodents via clinical studies.

    Our understanding of how acrylamide behaves in humans needs to be refined and then this knowledge should be applied to constructing stricter government guidelines.


    From an overview of the literature in this area, it is clear that the majority of authorities both recognise and call for a greater awareness of acrylamide as a potential mutagen and also call for more exploratory work on the subject.


    1. Abramsson-Zetterberg, L. (2003). The dose-response relationship at very low doses of acrylamide is linear in the flow cytometer-based mouse micronucleus assay. Mutat. Res. 2003 535, 215 - 222.
    2. Adler, I. D., Baumgartner, A B., Gonda, H G., Friedman, M. A., and Skerhut, M N. (2000). 1-Aminobenzotriazole inhibits acrylamide-induced dominant lethal effects in spermatids of male mice. Mutagenesis 2000 15, 133 - 136
    3. Barone G,Giancola CLilley T H,Mattia C A,Puliti R (2005)Enthalpies and entropies of fusion of some substituted dipeptides .Journal of Thermal Analysis and Calorimetry. Volume 38, Number 12
    4. Besaratinia A B, Pfeifer G B (2007) A review of mechanisms of acrylamide carcinogenicity. Carcinogenesis, March 1, 2007; 28 (3): 519 - 528.
    5. Besaratinia A B, Pfeifer GP. (2004) Genotoxicity of acrylamide and glycidamide. J Natl Cancer Inst 2004 ; 96 : 1023 - 9.
    6. Bolt H M. (2003) Genotoxicity-threshold or not? Introduction of cases of industrial chemicals. Toxicol. Lett. 2003 140 - 141 : 43 - 51.
    7. Calleman, C. J. (1996). The metabolism and pharmacokinetics of acrylamide: Implications for mechanisms of toxicity and human risk estimation. Drug Metab. Rev. 28, 527 - 590
    8. CSPI (2009), Center for Science in the public Interest, 25TH June 2002. Available at Accessed 8.4.2010.
    9. Doerge D R, da Costa G G, McDaniel L P, Churchwell M I, Twaddle N C, Beland F A. (2005) DNA adducts derived from administration of acrylamide and glycidamide to mice and rats. Mutat Res 2005 ; 580 : 131 - 41
    10. Dybing E F, Farmer P B, Andersen M N, et al. (2005) Human exposure and internal dose assessments of acrylamide in food. Food Chem Toxicol 2005 ; 43 : 365 - 410.
    11. Dybing E F, Sanner T B (2003) Risk Assessment of Acrylamide in Foods. Toxicological Sciences 75, 7 - 15 (2003)
    12. Eccles, M N. and Mason, J P. (2001) How to develop cost-conscious guidelines. Health Technology Assessment 5 (16), 1 - 78.
    13. Fennell T R, Sumner S C J, Snyder R W, Burgess J P, Spicer R O, Bridson E T, Friedman M A (2005) Metabolism and Hemoglobin Adduct Formation of Acrylamide in Humans. Toxicol. Sci., May 1, 2005 ; 85 (1) : 447 - 459.
    14. Fennema O R (2006) Food Chemistry, 5th Edition, 2006 CRC Press: Oxford ISBN-13 : 9780824796914
    15. Friedman M N. (2003) Chemistry, biochemistry, and safety of acrylamide. A review. J. Agr. Food Chem. 51 : 4504 - 4526.
    16. Friedman, M. A., Dulak, L. H., and Stedham, M. A. (1995). A lifetime oncogenicity study in rats with acrylamide. Fundam. Appl. Toxicol. 1995 27, 95 - 105
    17. Fuhr U V, Bottecher M I, Kinzig-Schippers M K, Weyer A D, Jetter A f, Lazar A K et al. (2006) Ingestion of a Defined Dose in a Test Meal to Improve Risk Assessment for Acrylamide Carcinogenicity. Cancer Epidemiology, Biomarkers & Prevention February 2006 15 ; 266 - 7
    18. Giese, J. Acrylamide in Foods. Food Technology 2002; 56(10), 71-72
    19. Ghanayem B I, Bai R B, Burka L T (2009) Effect of Dose Volume on the Toxicokinetics of Acrylamide and Its Metabolites and 2-Deoxy-D-glucose. Drug Metab. Dispos., February 1, 2009 ; 37 (2) : 259 - 263.
    20. Ghanayem B I, McDaniel L P, Churchwell M I, Twaddle N C, Snyder R P, Fennell T R, Doerge D R. (2005) Role of CYP2E1 in the epoxidation of acrylamide to glycidamide and formation of DNA and hemoglobin adducts. Toxicol. Sci. 2005 88 : 311 - 318
    21. Granath F A, Tornqvist M N (2003) Who Knows Whether Acrylamide in Food Is Hazardous to Humans? J Natl Cancer Inst, June 18, 2003 ; 95 (12) : 842 - 843.
    22. Hogervorst J G, Schouten L J, Konings E K, Goldbohm R A, van den Brandt P A (2008) Dietary acrylamide intake and the risk of renal cell, bladder, and prostate cancer. Am. J. Clinical Nutrition, May 1, 2008 ; 87 (5) : 1428 - 1438.
    23. International Agency for Research on Cancer [IARC] (1994). Acrylamide. IARC Monogr. Eval. Carcinog. Risks Hum 1994 . 60, 389 - 433
    24. LoPachin RM. (2004) The changing view of acrylamide neurotoxicity. Neurotoxicology 2004 25 : 617 - 630
    25. Maillard L C (1913) Réaction générale des acides aminés sur les sucres. Journal de Physiologie, 1913 tome 14 page 813;
    26. Manière I T, Godard T B, Doerge D R, Churchwell M I, Guffroy M N, Laurentie M B, Poul J M. (2005) DNA damage and DNA adduct formation in rat tissues following oral administration of acrylamide. Mutat. Res. 2005 580 : 119 - 129.
    27. Martins C G, Oliveira N J, Pingarilho M P, Gamboa da Costa G A, Martins V D, Marques M N, Beland F A, Churchwell M I, Doerge D R, Rueff J P, et al. (2007) Cytogenetic Damage Induced by Acrylamide and Glycidamide in Mammalian Cells: Correlation with Specific Glycidamide-DNA Adducts. Toxicol. Sci., February 1, 2007 ; 95 (2) : 383 - 390.
    28. Mucci L A, Sandin S O, Balter K P, Adami H O, Magnusson C D, Weiderpass E M (2005) . Acrylamide intake and breast cancer risk in Swedish women. JAMA 2005 ; 293 : 1326 - 7
    29. Mucci L A, Lindblad P C, Steineck G B, Adami H O. (2004) Dietary acrylamide and risk of renal cell cancer. Int J Cancer 2004 ; 109 : 774 - 6
    30. -tles S, -tles S. Acrylamide in Food. Chmeical Structure of Acrylamide. EJEAFChe, 3 (5), 2004 : 723-730
    31. Reynolds T (2002) Acrylamide and Cancer: Tunnel Leak in Sweden Prompted Studies. Journal of the National Cancer Institute, 2002 Vol. 94, No. 12, 876 - 878
    32. Rice J M. (2005) The carcinogenicity of acrylamide. Mutat Res 2005 ; 580 : 3 - 20
    33. Richmond, P, Borrow, R. Acrylamide in Food. The Lancet 2003; 361(2) : 361-362
    34. Sanner, T O., Dybing, E T., Willems, M. I., and Kroese, E. D. (2001). A simple method for quantitative risk assessment of non-threshold carcinogens based on the dose descriptor T25. Pharmacol. Toxicol. 2001 88, 331 - 341.
    35. Semih, -. (2007). Case Studies in Food Safety and Environmental Health. Springer US. Part I. 3-9.
    36. Svensson, K., Abramsson, L., Becker, W., Glynn, A., Hellenas, K., Lind, Y., Rosen, J. Dietary intake of acrylamide in Sweden. Food and Chemical Toxicology, 2003; 41: 1581-1586
    37. SNFA (2002) Swedish National Food Agency. Press conference. Uppsala, 24 April 2002. Available at Accessed 9.3.2010
    38. Sobel, W C., Bond, G. G., Parsons, T. W., and Brenner, F. E. (1986). Acrylamide cohort mortality study. Brit. J. Ind. Med. 1986 43, 785 - 788
    39. Sörgel F T, Weissenbacher R M, Kinzig-Schippers M N, et al. (2002) Acrylamide : increased concentrations in homemade food and first evidence of its variable absorption from food, variable metabolism and placental and breast milk transfer in humans. Chemotherapy 2002 ; 48 : 267 - 74
    40. Stadler R H, Blank I J, Varga N P, et al. (2002) Acrylamide from Maillard reaction products. Nature 2002 ; 419 : 449 - 50.
    41. Sumner S C, Fennell T R, Moore T A, Chanas B C, Gonzalez F T, Ghanayem B I. (1999) Role of cytochrome P450 2E1 in the metabolism of acrylamide and acrylonitrile in mice. Chem Res Toxicol 1999 ; 12 : 1110 - 6.
    42. Sumner, S. C., MacNeela, J. P., and Fennel, T. R. (1992). Characterization and quantitation of urinary metabolites of [1,2,3-13C] acrylamide in rats and mice using 13C nuclear magnetic resonance spectroscopy. Chem. Res. Toxicol. 1992 5, 81 - 89
    43. Swaen G M H, Haidar S O, Burns C J, Bodner K O, Parsons T F, Collins J K, Baase C D (2007) Mortality study update of acrylamide workers, ccup. Environ. Med., June 1, 2007; 64 (6) : 396 - 401.
    44. Tareke E T, Rydberg P A, Karlsson P O, Eriksson S O, Tornqvist M D. (2002) Analysis of acrylamide, a carcinogen formed in heated foodstuffs. J Agric Food Chem 2002 ; 50 : 4998 - 5006.
    45. Thulesius O J, Waddell W J (2004) Human exposures to acrylamide are below the threshold for carcinogenesis. Human and Experimental Toxicology, July 1, 2004 ; 23 (7) : 357 - 358.
    46. Tsuda H P, et al. (2003) Acrylamide ; induction of DNA damage, chromosomal aberrations and cell transformation without gene mutations. Mutagenesis 2003 8 : 23 - 2 9
    47. Tyl, R, Crump, K. Acrylamide in Food. Food Standards Agency 2003; 5 : 215-222
    48. Tyl, R. W., Friedman, M. A., Losco, P.E., Fisher, L. C., Johnson, K. A., Strother, D. E., and Wolf, C. H. (2000). Rat two-generation reproduction and dominant lethal study of acrylamide in drinking water. Reprod. Toxicol. 2000 14, 385 - 401.
    49. Vattem, A, Shetty, K. Acrylamide in Food: a Model for Mechanism of Formation and its Reduction. Innovative Food Science and Emerging Technologies 2003; 4: 331-338
    50. WHO (2005) World Health Organization. Summary Report of the Sixty-Fourth Meeting of the Joint FAO/WHO Expert Committee on Food Additive (JECFA) pp. 1-47 Rome, Italy. The ILSI Press International Life Sciences Institute, Washington DC
    51. Zhang L T , Moo-Young M D, Chou C P (2008) Stability Improvement of a Therapeutic Protein by Reducing Agent Pre-treatment. Chinese Journal of Biotechnology. (2008) Vol 24, Issue 12 December 2008, Pages 2142 - 2143