Manfred Lützow is FAO Secretary of the Joint
FAO/WHO Expert Committee on Food Additives (JECFA).
"Fried, oven-baked and deep-fried potato and cereal products may contain high levels of acrylamide", which is a "probable human carcinogen". These first lines of a press release issued by the Swedish National Food Agency on 24 April 2002 alarmed consumers, scientists and regulators alike with the question: what is the risk from eating French fries, potato chips or Scandinavian crisp bread? Even more alarming was the suggested conclusion that "perhaps several hundred of the annual cancer cases in Sweden can be attributed to acrylamide", which would equate to hundreds of thousands of cancers worldwide being caused by a contaminant occurring in foods that are consumed daily by many people. The following weeks saw calls for rapid actions, consumers asking for recommendations on which foods they should avoid, food manufacturers trying to understand this new food scare and to assess the impact on their business. On the initiative of the World Health Organization (WHO), in July a Joint FAO/WHO Consultation on Health Implications of Acrylamide in Food tried to provide initial answers to some of these questions. However, to understand better the conclusions and recommendations of the participating experts, it is helpful to review briefly what was known about acrylamide before the news release early in 2002.
Acrylamide is a small molecule with one interesting property: it is highly reactive, which means it easily binds to other molecules (see Figure 1). This property gives it a dual nature as both an indispensable industrial chemical and a toxic compound known to cause harm to animals and humans. More than 250 000 tonnes of this substance are annually used in a variety of applications that exploit the property of acrylamide molecules to react with each other, a process known as polymerization The resulting polyacrylamides form a family of highly water-soluble and stable polymers with tailor-made properties, which are suitable as additives for water treatment, flocculants, thickeners, soil conditioning agents, sewage and waste treatment and en hanced oil recovery. Acrylamide is also used in the synthesis of other chemical products, among them dyes and contact lenses, and for building projects such as dam foundations and tunnels where concrete must harden in the presence of water. A small amount of acrylamide is used for an application which has radically changed our knowledge about life: research in modern biotechnology would not have progressed as rapidly without the use of polyacrylamide gel electrophoresis (PAGE), a method that uses flat gels of polyacrylamide to separate and isolate DNA and other biomolecules.
Due to the increased industrial use of acrylamide, toxicologists became interested in the compound because of effects seen in workers with frequent exposure to the substance. Studies and observations in animals and humans revealed that the high reactivity of acrylamide was causing a variety of serious harmful effects such as drowsiness, impaired coordination, hallucinations, confusion, abnormal sensations and muscle weakness. These effects indicated that inhaling acrylamide vapour leads to neurological disorders. These neurotoxic reactions were also observed in laboratory animals exposed to comparatively higher levels, in the range that causes cancer. A long-term study was conducted involving more than 8 000 workers who had inhaled acrylamide regularly at their working place before the toxicity had been fully recognized. The results of this study did not show increased levels of cancer. However, epidemiologists and toxicologists agree that this negative finding cannot be taken as a proof that acrylamide will not cause cancer in humans, because the sample size may have been too small to detect cancer. Further studies have revealed that acrylamide is able to modify genetic material in bacteria and animals.The known toxicity and the large-scale use of acrylamide require strict controls of products containing the chemical, as well as protection for humans exposed to it. WHO recommended in 1985 that the concentration in workroom air should not exceed 0.1 g/m3. Similar limits were adopted and enforced by national authorities. The use of polyacrylamide containing additives in the purification of drinking-water was considered to be a potential hazard because free acrylamide could be dissolved; WHO suggested that a guideline value for tap water should be set at 0.5 µg/l, a value which could be controlled using suitable analytical methods. Acrylamide for industrial or laboratory use is classified as a potential carcinogen and must carry appropriate warning signals and statements such as those shown in Figure 2. The question whether acrylamide could also contaminate food was raised at the beginning of the 1990s when the British Central Science Laboratory developed an analytical method to determine the presence of the substance in tomatoes grown in a synthetic medium; no alarming levels were found at that time.
Sample warnings on industrial
products containing acrylamide
After a phase of intensive research, both scientists and regulators considered acrylamide to be one of the many hazardous compounds needed by industrial societies for a variety of purposes and which - if controlled properly - should put humans only at a small and limited risk. Appropriate controls appeared to be in place.
New concern was raised in Sweden in 1997, during the construction of a tunnel near Hallandsåsen near the southern coast, when the effects of a grouting agent containing acrylamide were signalled: "Adverse effects symptomatic of acryl-amide poisoning were observed in cows and fish downstream [from] the construction work" (European Environment Agency, 1998). By coincidence, in the same year a similar event occurred in Norway, which provoked suspicion among the media and the public in Scandinavia about whether acrylamide use was under proper control.
A group at the University of Stockholm shared these concerns, but they also had to answer a question that was raised by the event at Hallandsåsen: How should the quantity of acrylamide that had been inhaled or absorbed (via the skin) by the tunnel workers (some of whom had shown weak, temporary signs of intoxi-cation) be measured? The method currently used analyses red blood cells, because they are so easily available. This method exploits the high reactivity of acrylamide with organic molecules - in this case haemoglobin, the oxygen carrier for red blood cells. Acrylamide binds to haemoglobin, forming "adducts", the level of which can be reliably determined. Since red blood cells are eliminated from the blood after approximately four months, the measured level reflects the exposure of an individual to the compound over the four-month period.
In attempting to find a relation between the amount of acrylamide absorbed by workers and their blood levels of adducts, the scientists at the University of Stockholm confirmed previous findings of a "normal background range" with levels being far lower than those observed in tunnel workers exposed to acrylamide (Hagmar et al., 2001). However, the group led by M. Törnqvist was the first to investigate systematically the source of the acryl-amide for this background level of acryl-amide in the normal population. Smoking was a known cause, but it would not explain background levels in non-smokers. A study in rats revealed a possible source: a group receiving a fried-feed standard diet for one or two months showed significantly higher levels than rats fed a non-fried diet. Subsequently, acrylamide was detected in the fried feed at levels high enough to explain the observed background. These results had already been reported two years earlier in an article entitled "Acrylamide - a cooking carcinogen?" (Tareke et al., 2000). However, at the time, neither the media nor the public showed much concern.
The Swedish health authorities were informed about the new preliminary findings, and they decided to perform a more extensive survey of human food using their own newly developed analyti-cal method. The analytical determination of acrylamide is difficult; until recently, methods of choice required transforming the molecule into a derivative to allow reliable quantification. Although derivatization is a well-established, reliable analytical technique, the National Food Administration in Stockholm decided to determine acrylamide amounts directly using a more sophisticated and expensive method. News of the availability of this new method and a first preliminary set of data from fried "starchy" food were released in April 2002. Project leader Karl-Erik Hellenäs and his group con-firmed previous findings, which had not previously received particular media attention. However, this time the data created a huge impact at a specifically convened press conference. The news that a bag of French fries contained 500 times more cancer-causing compound than WHO standards allowed in the same amount of drinking-water spread rapidly, and first in Sweden, where consumers demanded specific information about which food brands they should avoid, then in other countries where questions were posed about what consumers and food industry professionals should do when buying or preparing food.
A growing number of puzzled national authorities started to address such concerns by rapidly looking into the available data and commissioning analytical work, and very early, following a suggestion from WHO, an expert consultation was convened jointly by FAO/WHO to discuss the health aspects of acrylamide in food, to be held two months after the April 2002 press conference. Twenty-five renowned scientists tried to answer the critical questions in three days of interdisciplinary work. They had access to the newest data and they took into consideration the body of work which has been accumulating over the years. The results are an important snapshot of our current understanding of the problem, which should continue to develop and improve. Understanding the urgency of the meeting and the needs of the public, the experts agreed not only to the full report (FAO/WHO, 2002), they also discussed and released a short, one-page executive summary (see Box 1), which provided initial rapid answers to the main questions.
But what is the experts' answer to the question raised by the title of this article? What is the risk of the presence of acryl-amide in food for consumers? The story of the use of acrylamide as a synthetic chemical and the surprising discovery that it occurs naturally in foods treated at high temperatures raise a complex issue. The risk is not new. Baking certain types of breads, frying potato chips, preparing Swiss Rösti have, presumably, been accompanied by the formation of acryl-amide since preparation of these foods began centuries ago. And there are other chemicals like benzo[a]pyrene, formed during grilling or frying, which have been recognized as potential cancer-causing agents of similar potency. However, reported levels of acrylamide are higher than those for other contaminants, although a quantitative answer to the question is difficult to provide. The experts convened in Geneva were unable to agree in the short time available during the meeting.
In order to understand this difficulty, it is first necessary to understand that the concept applied in the risk assessments of compounds like acrylamide is different than for most other chemicals. Following the empirical postulate of Paracelsus that "the dose defines the poison", toxicology - specifically food toxicology - has applied the assumption that a certain dose is required to observe an adverse effect, and that above a threshold amount, toxic reactions should be observed within a certain probability range. Consequently, a level where no effects are seen should also exist; this is called the no-observed-adverse-effect level (NOAEL). Below this level, absence of toxic reactions is explained by the capability of human metabolism to detoxify the hazardous chemical. This concept is not merely theoretical, it has been used effectively to describe the majority of chemicals which have been assessed since committees like the Joint FAO/WHO Expert Committee on Food Additives (JECFA) started to carry out their work.
The usefulness of the "dose-response curve" was challenged by the discovery of the structure of DNA and the understanding of how this large molecule is modified by mutations induced by using "genotoxins" like acrylamide. Hypothetically, very low concentrations of a genotoxin, even one single molecule, could induce a change in DNA that could possibly lead to the development of cancer later. Although this concept has not yet been sufficiently established through observation, the idea that some poisons may not obey Paracelsus' theory is not easy to defend, because animal tests are not sensitive enough to detect and to quantify induction of cancer at such low levels. When, in an animal study, effects are observed at all levels administered, toxicologists can not quantify safe levels of intake; however, society requests an assessment of the risk in order to be able to understand its extent. The answer provided by toxicologists in such a case is very often a different one: the "safe level" of intake is not defined; rather, the number of "possible adverse effects", e.g. cases of cancer in a human population, is estimated. The mathematical models used for this purpose derive their figures from animal data. They require a certain set of assumptions: by varying the factors the resulting so-called "quantitative risk assessment" may vary by several orders of magnitude. It is easy to imagine that public reaction will be different depending upon whether the outcome predicted is one, ten, a hundred or a thousand additional cases of cancer in a population of one million. Estimating hypothetical additional cancer cases - numbers which can never be proven - is a job requiring a careful and comprehensive analysis of available data. And it is important to express and communicate the level of uncertainty linked to such a simple figure. The use of these figures by risk managers, moreover, serves a different purpose: whereas a safe range of intake permits regulators to set maximum levels for specific foods such as food additives, which are perceived virtually as safe, the decision to accept certain levels of contaminants which are possibly linked to an additional number of cancer cases is more difficult, and it is not easy to communicate such decisions accordingly.
With the current knowledge available, it is impossible to say whether the estimate published by the Swedish food authority - that perhaps several hundred of the annual cancer cases in Sweden can be attributed to acrylamide - is correct. De-pending on the data used and the mathematical model applied, different (usually far lower) figures can be extrapolated. The current unsatisfactory answer to the question of the risk posed by acrylamide in foods is that it remains unknown. The consultation organized by FAO and WHO identified a number of questions for which adequate answers are not yet available. They relate, for example, to the formation and possible disappearance of acrylamide in food, the levels occurring in foods from different types of diets, the mechanism by which acrylamide and its metabolites cause cancer, and the correlation between adducts to haemoglobin and acrylamide exposure.
To the question of how acrylamide is formed during cooking, an initial response was provided by two research teams just six months after the Swedish authorities had announced their findings (Mottram, Bronislaw and Dodson, 2002; Stadler et al., 2002). They identified a specific "Maillard reaction" in model food systems: this re-action involves the amino-acid asparagine and glucose as probable precursors. The products of this very complex chemical reaction are primarily responsible for the colour and flavour that are formed during baking and frying. Other Maillard reactions are known to produce toxic substances, and future work will show whether a reduction of acrylamide levels can be achieved without affecting negatively the look and taste of foods.
The occurrence of acrylamide at unexpected high levels in commonly consumed foods in many countries is of major concern; this concern is based on what is currently known and what is not known about the possible effects on humans of such levels in foods. It is known that acrylamide can damage DNA in bacteria and animals, that animals develop various types of cancer when exposed to high levels of acrylamide, that animals and humans form haemoglobin-adducts after exposure to acrylamide. It is not known whether there is a threshold of exposure below which the probability of cancer formation is markedly reduced. For humans, it is also not well understood how many cancer cases could be caused by those levels of acrylamide observed in food; it is also not sufficiently known what types of food possibly contain acrylamide, and with what levels.
In view of these uncertainties the FAO/WHO consultation still recommended that some principles should be applied.
The consultation asked FAO and WHO to establish an international network, "Acrylamide in Food", to accelerate the formation of a more comprehensive database by inviting all interested parties to share relevant data as well as ongoing investigations. It is hoped that this database, which has been established in collaboration with the Joint Institute for Food Safety and Applied Nutrition (JIFSAN) at the University of Maryland, will in due course enable scientists to provide governments, the food industry and consumers with more specific advice.
Announcing the Acrylamide Infonet
FAO/WHO Consultation on the Health
THE FAO/WHO CONSULTATION ON THE HEALTH IMPLICATIONS OF ACRYLAMIDE IN FOOD has undertaken a preliminary evaluation of new and existing data and research on acrylamide. The following main conclusions were reached.
European Environment Agency (EEA). 1998. EEA Information Procedure on Draft Technical Regulations. Annex II, Chapter XIX, 1: EEA Agreement. Notification slip 98/9034/N, submitted by Norway in 1998.
Hagmar, L., Törnqvist, M., Nordander, C., Rosén, I., Bruze, M., Kautiainen, A., Magnusson, A.-L., Malmberg, B., Aprea, P., Granath, F. & Axmon, A. 2001. Health effects of occupational exposure to acrylamide using hemoglobin adducts as biomarkers of internal dose. Scand. J. Work Environ. Health, 27(4): 219-226.
Mottram, D.S., Bronislaw L.W. & Dodson, A.T. 2002. Acrylamide is formed in the Maillard reaction. Nature, Oct., 419: 448.
Stadler, R.H., Imre Blank, N., Varga, F.R., Jörg Hau, P.A., Guy, M.-C.R. & Riediker, S. 2002. Acrylamide from Maillard reaction products. Nature, Oct., 419: 449.
Tareke, E., Rydberg, P., Karlsson, P., Eriksson, S. & Tornqvist, M. 2000. Acrylamide: a cooking carcinogen? Chem. Res. Toxicol., 13(6): 517-522.
FAO/WHO. 2002. Health implications of acrylamide in food. Summary Report of a Joint FAO/WHO Consultation, Geneva (Switzerland), 25-27 June 2002 (www.who.int/fsf/Acrylamide/SummaryreportFinal.pdf)
FAO/WHO Acrylamide in Food Network (Acrylamide Infonet): www.acrylamide-food.org
American Association of Cereal Chemists (AACC): www.aaccnet.org/acrylamide
National Food Authority (Sweden): www.slv.se
WHO - Food safety: www.who.int/fsf/
ACRYLAMIDE, A WELL-KNOWN TOXIC SUBSTANCE that is classified as a potential cancer-causing agent in humans, has recently been discovered in a variety of foods prepared at high temperatures, such as potato chips, French fries and breads. These unexpected findings have alarmed consumers, regu-lators and the food industry. Acrylamide, widely used in the industrial manufacturing of plastics, is a well-investigated compound that has been shown to induce cancer in test animals and neurological disorders in humans.
L'ACRYLAMIDE, SUBSTANCE TOXIQUE BIEN CONNUE et répertoriée comme cause potentielle du cancer chez l'homme, a été récemment décelée dans une variété d'aliments préparés à hautes températures, tels que les chips, les frites et le pain. Ces découvertes inattendues ont alarmé les consommateurs, les autorités de réglementation et l'industrie alimentaire. L'acrylamide, utilisée en grande partie dans la fabrication industrielle de plastiques, est une substance bien étudiée, qui provoque des cancers chez des animaux de laboratoire, ainsi que des dysfonctionnements neurologiques chez l'homme. Suite à cette information, l'exposition des travailleurs de l'agroalimentaire a été étudiée dans les détails et effectivement contrôlée durant de nombreuses années. L'exposition accidentelle à l'acrylamide chez des travailleurs du bâtiment et des animaux de ferme au cours d'un récent projet pour la construction d'un tunnel en Suède a permis de reporter l'attention des scientifiques sur les effets toxiques de l'acrylamide et de découvrir cette substance dans les aliments.
RECIENTEMENTE SE DESCUBRIO LA PRESENCIA DE ACRILAMIDA, sustancia tóxica bien conocida que está considerada como un agente cancerígeno para los seres humanos, en diversos alimentos que se preparan a altas temperaturas, como las patatas fritas y el pan. Este descubrimiento inesperado ha alarmado a los consumidores, a los órganos de reglamentación y a la industria alimentaria. La acrilamida, cuyo uso está muy extendido en la fabricación industrial de plásticos, es un compuesto bien investigado que se ha demostrado que produce cáncer en animales de experimentación y trastornos neurológicos en los seres humanos. Como resultado de este descubrimiento, se ha estudiado ampliamente y controlado eficazmente la exposición de los trabajadores industriales durante muchos años. La exposición accidental a la acrilamida de trabajadores de la construcción y de animales domésticos durante el reciente proyecto de un túnel en Suecia volvió a concentrar la atención científica en los efectos tóxicos de la acri lamida, lo que posteriormente llevó a su descubrimiento en los alimentos.