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.
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
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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.
Acrylamide 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 mutageneic. 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.
This review is designed to present an overview of the evidence base supporting the elements relating to the health implications for ingested acrylamide.
Summary & Methodology of the literature review
This review set out to discover the background to acrylamide, to understand and present how it was formed and how it arrives in the human food chain. It then sought to consider 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.
These aims were achieved by an extensive searching of the available database.
Searching of these databases took place at local University reference library, the local post-grad clinical library (client to personalise here). 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.
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.
What is 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,
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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)
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 120Â°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 Î¼g/kg body weight, with 0.5 Î¼g/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 Î¼g/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).
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 research, 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)
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 Â°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.
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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 Â°C, especially in baked or fried products (French fries). When frying below 180 Â°C acrylamide is not formed. (Fennema O R 2006)
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 mutageneic (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 - see above) 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 evidence level IIa Friedman study almost verbatim:
Using the conservative default linear extrapolation methods LED10 and T25 for genotoxic carcinogensâ€¦.. the lifetime cancer hazard after lifelong exposure to 1 Âµg 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.â€¦â€¦ corresponding to 6 cancer cases per 10,000 individuals. For the 10% and 2.5% males with the highest intakesâ€¦â€¦ lifetime cancer risks were estimated to 13 and 21 cancer cases per 10,000 individuals. For females, the risk values were slightly lower. (Friedman, M. A et al. 1995)
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 Î¼g acrylamide with the food was in the order of magnitude of 1 Ã- 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 in this essay, 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 hemoglobin 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)
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.
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 southwestern 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 were 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 Âµg acrylamide per day in males and females, respectively, which correlates to intake doses of about 0.49 and 0.46 Âµg 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 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)
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 Âµg/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 Âµg/kg/body wt, and as high as 5.1 Âµg/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 is estimated to be on average between 1 and 4 Âµg/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)
As an illustrative example, one can note that potato chips range from 330 to 2300 micrograms (mg) 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 level 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 Âµg 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 Âµg 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)
Discussion & Conclusions
The issues relating to the mutageneic effects of acrylamide are both complex and not yet 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. Because acrylamide appears to have a long lead time between exposure and any mutageneic activity, the last major mass exposure was in Sweden only 13 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 detoxication 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 levels of acrylamide in drinking water in the EEC are 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 Âµg/kg/body wt of acrylamide for the general population of adults. An intake of 1 Âµg 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 mutageneic in the human model. The actual dose/effect relationship has not yet been reliably defined. It is believed that acrylamide exerts a mutageneic 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.
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.
Classification of evidence levels
Evidence obtained from meta-analysis of randomised controlled trials.
Evidence obtained from at least one randomised controlled trial.
Evidence obtained from at least one well-designed controlled study without randomisation.
Evidence obtained from at least one other type of well-designed quasi-experimental study.
Evidence obtained from well-designed non-experimental descriptive studies, such as comparative studies, correlation studies and case studies.
Evidence obtained from expert committee reports or opinions and/or clinical experience of respected authorities.
(After Eccles M et al. 2001)
(After Eccles, M 2001)