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Une évaluation globale de l'impact des contaminants de type mycotoxines sur la sécurité alimentaire

What are the tasks of the FAO/WHO2 Conference on food additives?

    The tasks of the Joint FAO/WHO Conference on Food Additives (JECFA) are to elaborate principles governing the evaluation of food additives and food contaminants and to undertake their toxicological evaluation and dietary exposure estimation.

    The Committee considers that model estimates cannot rely solely on empirical guidance on performing dose–response analyses and stressed the need to use toxicological knowledge, weight of evidence and other information. Therefore, it takes specifically into consideration the Principles and Methods for the Risk Assessment of Chemicals in Food published in 2009. On this basis, dose–response modelling and exposure-related effects were evaluated to establish a health-based guidance value or a margin of exposure (MOE) for risk assessment.

    2 FAO – Food & Agriculture Organisation

    What are mycotoxins?

      Mycotoxins are poisonous substances produced by fungi – a group of organisms that contains moulds, yeasts and mushrooms. Two closely related species of moulds or fungi are mainly responsible for producing the mycotoxins of public health significance: Fusarium and Aspergillus( flavus and Aspergillus parasiticus), that produce fumonisins and aflatoxins, respectively.

      Several types of aflatoxin (14 or more) occur in nature, but four – aflatoxins B1, B2, G1 and G2 are particularly dangerous to humans and animals.

      A number of different types of fumonisin are known, but fumonisins B1, B2 and B3 (also named FB1, FB2 and FB3) are the major forms found in food.

      While aflatoxins are known to cause cancer of the liver in humans, fumonisins are thought to be possible cancer promoters of aflatoxin carcinogenicity. For fumonisins the evidence for adverse health effects in humans is currently inconclusive but there are concerns they may contribute to various serious adverse health outcomes such as birth defects.

      There is some evidence and concern that there might be additive or synergistic actions that occur when the two types of mycotoxins are present, potentially increasing carcinogenicity, in particular to cause cancer of the liver in humans.

      Fumonisins can also have significant health effects in livestock and other animals and aflatoxins pose a significant economic burden, causing an estimated 25% or more of the world’s food crops to be destroyed annually.

      What are the food products that can contain mycotoxins?

        The fungi Fusarium verticillioides, F. proliferatum and F. fujikuroi, as well as some less widespread Fusarium species, which occur worldwide, are typically found under favorable conditions, such as high temperatures and high humidity in tropical and subtropical regions. Normally found on dead and decaying vegetation, these can invade food crops and are common contaminants of maize, and to a lesser extent of wheat and other cereals including their derived products. Their mycotoxins fumonisins are frequent contaminants of maize and, to a lesser extent, of rice, sorghum, wheat, and cereal-based foods prepared from these commodities.

        Aflatoxins, but not fumonisins, are also common contaminants of ground nuts (e.g. peanuts) and tree nuts (e.g. almonds, pistachios, Brazil nuts), and exposure to both mycotoxins is more likely in areas where these foods are routinely consumed. Drought stress, insect damage and poor storage conditions can also contribute to higher occurrence of the moulds, including in more temperate regions.

        Co-exposure can either occur from the same food being contaminated with both mycotoxins, or within the diet/meal from different foods each contaminated with one or the other.

        Dairy milk and its processed products follow the same geographic pattern of aflatoxins contamination, with a number of samples reported above the maximal level of contamination set by the Codex Alimentarius Commission. The presence of a specific aflatoxin in human milk is a more complex issue, in that it occurs also as a consequence of maternal exposure to a different aflatoxin. This exposure is minimal in developed countries but can be problematic in rural subsistence farming areas of developing countries.

        Food crops can become contaminated both before and after harvesting. Pre-harvest contamination with aflatoxins is mainly limited to maize, cottonseed, peanuts and tree nuts. Post-harvest contamination can be found in a variety of other crops such as coffee, rice and spices. Improper storage under conditions that favor mould growth (warm and humid storage environments) can typically lead to levels of contamination much higher than those found in the field.

        How much are humans and animals exposed to mycotoxins?

          National estimates of dietary exposure to aflatoxins indicate differences between developed and developing countries. In developed countries, mean aflatoxin dietary exposures are generally less than 0.001 μg/kg body weight (bw) per day3 whereas estimates for some sub-Saharan African countries exceed 0.1 μg/kg bw per day, although these latter estimates are often based on very few data.

          In national evaluations from a few countries in 2011–2016, the mean exposure to fumonisins was generally below 0.25 μg/kg bw per day in European countries. The highest exposures to fumonisins were recorded to be as high as 15 μg/kg bw per day in Malawi. The highest national exposures to fumonisins were observed in the youngest age groups.

          Maize is the predominant source of exposure to fumonisins in most cluster diets and can lead to very high exposures in areas where maize is the main food source and contamination levels can be very high. Wheat can be an important contributor to exposure to fumonisins in those clusters where wheat is an important food source and less maize is consumed.

          At an ML of 4 μg/kg, which is the strictest maximal level proposed by the Codex Alimentarus, the proportion of the world market of ready-to-eat peanuts rejected would be approximately double the proportion rejected at an ML of 15 μg/kg (about 20% versus 10%). However, JECFA concluded that enforcing maximum levels of below 15 µg/kg for ready-to-eat peanuts would have little impact on dietary exposure to aflatoxin T for the general population4.

          3 One μg(or microgram) is one millionth of a gram
          4 Joint FAO/WHO Expert Committee on Food Additives.
           Eighty-third meeting November 2016 Summary and conclusions

          What are the potential effects of aflatoxins on human and animal health?

            Large doses of aflatoxins lead to acute poisoning that can be life threatening, usually through damage to the liver. Outbreaks of acute liver failure (jaundice, lethargy, nausea, death) linked to aflatoxins have been observed in human populations since the 1960s. Adults are more tolerant to acute exposure than children. The consumption of food containing aflatoxin concentrations of 1 mg/kg or higher has been suspected to cause aflatoxicosis.

            Long-term or chronic exposure to aflatoxins has several health consequences:

            • aflatoxins are among the most mutagenic (DNA damaging) and carcinogenic substances known to cause liver cancer and have also been linked to other types of cancer;  
            • aflatoxins have the potential to cause birth defects in children, who may also become stunted, although these has yet to be confirmed because other factors also contribute to growth faltering, e.g. low socioeconomic status, chronic diarrhea, infectious diseases or malnutrition. Epidemiological data available support the hypothesis that aflatoxin exposure in utero and during early life has negative effects on growth; in particular, decreased height is the most frequently observed symptom; 
            • aflatoxins cause immunosuppression, resulting in decreased resistance to infectious agents (e.g. HIV, tuberculosis).

            Based on past outbreaks it has been estimated that, when consumed over a period of 1–3 weeks, a dose of 20–120 μg/kg bw per day of aflatoxin B1 (AFB1) is acutely toxic and potentially lethal.

            The Committee also evaluated the effects of aflatoxins on domestic animal health and productivity in cattle, poultry, and swine genotypes used in North America and Western Europe. In animals, aflatoxins cause a variety of adverse effects, in general liver and kidney problems. Pigs and cattle, where milk production is reduced, are also highly affected, and in chickens the effects of aflatoxins include liver damage, impaired productivity and reproductive efficiency, increased susceptibility to disease, as well as various effects on the eggs.

            What makes aflatoxin B1 toxic?

              To eliminate foreign compounds, the body usually transform them in compounds (or “metabolites”) that are more soluble in water and thus more easily excreted in urine. When the body deals that way with aflatoxin, it transforms it into a form (epoxide) that reacts quickly with DNA and proteins, disrupting the functioning of cells and organs5. In the case of aflatoxins, the damage caused is usually to that organ.

              Different species deal with that reactive metabolite with differing success, and that is why for instance rats and mice are relatively resistant to aflatoxin B1, whereas trout are highly susceptible. Further detoxification of AFB1-epoxide is due to a family of enzymes called glutathione S-transferases (GST), which are present in the liver. The type of GST that are present in a species (including humans) or even in different individuals within the same species appears to be central to the interspecies differences in susceptibility to AFB.

              5 Evaluation of certain contaminants in food pg 13 and forty-ninth meeting of JECFA (Annex 1, reference 131)

              What are the potential effects of fumonisins on human and animal health?

                What we know of the toxicity of fumonisins on humans is mainly inferred from the effects on animals. In all animal species tested, fumonisin B1 has been associated with a wide range of adverse health effects, particularly on the liver and kidney.

                For fumonisins, observations on the health effects of the toxins on humans are limited. The current evidence to date indicates that fumonisins are not acutely toxic but further studies to investigate the association of fumonisins exposure with cancer risk, child growth impairment, and neural tube defects in humans are needed.

                A particular concern is the carcinogenic potential of the toxins and the possible indirect mutagenicity (DNA damage) although to date, the weight of evidence indicates that fumonisins are neither directly mutagenic nor metabolized into DNA reactive compounds.

                Another concern is the potential immunotoxicity of fumonisins; depression of specific and nonspecific immune response has been observed in pigs and mice at low oral doses, but the data are inconclusive.

                Fumonisins have also been observed to have effects on reproductive performance in pigs and rabbits, and birth defects – neural tube defects – have been induced in mice in a few studies.

                Concerning the potential neurotoxicity of fumonisins, while the toxins can induce leuko-encephalomalacia (softening of brain tissue) in horses (equids), it is considered unlikely that fumonisins cross the blood–brain barrier and induce neurotoxic effects in the brain; rather, in equids, they are thought to act via disruption of vascular function likely to be caused by accumulation of certain specific metabolites in the blood.

                In pigs, pulmonary edema caused by fumonisins has also been linked to altered vascular function.

                Are there interactions between aflatoxins and fumonisins in their effects on human health?

                  The health concerns of interactions between the two types of toxin include possible antagonistic, additive or synergistic effects. Evidence from laboratory animals and from in vitro studies simply suggests an additive or synergistic effect of fumonisin and aflatoxin co-exposure on the development of precancerous lesions or liver cancer. There are however currently few reports on dietary co-exposure and thus not yet adequate information and understanding of the role of interactions between aflatoxins and fumonisins in human disease and the extent of co-exposure as a contributing factor in human disease. Therefore, it is difficult to have a clear picture of the risks related to their combined exposure.

                  What are the maximum levels of food contamination allowed for aflatoxins?

                    The Codex standards set the maximum levels for contaminants and natural toxins such as mycotoxins in food and are the reference for the international trade in food. In various nuts, grains, dried figs and milk the maximum levels of contamination allowed are in the range of 0.5 to 15 μg/kg. For fumonisins, the maximum levels in grain from raw maize and maize flour and meal are 4000 and 2000 μg/kg, respectively.

                    How are contamination standards verified?

                      As exposure to aflatoxins needs to be kept as low as possible to protect the consumer as aflatoxins damage health but also because they pose a significant economic burden, causing an estimated 25% or more of the world’s food crops to be destroyed annually.

                      Countries, and in particular importing countries, are imposing increasingly more stringent regulations governing aflatoxins in food with maximal levels based on the Codex recommendations and most have also maximum permitted or acceptable levels for different foodstuff based on its Codes of practices, which detail appropriate measures to prevent and reduce the risk of aflatoxins in food and feed.

                      It is to this end that the WHO collects food contamination data from nationally recognized institutions and, through the Food Contamination Monitoring and Assessment Programme of the WHO Global Environment Monitoring System, commonly known as the GEMS/Food contaminants database, informs then the Codex Alimentarius Commission, the governments and other relevant institutions, as well as the public, on levels and trends of mycotoxins contaminants in food.

                      The GEMS/Food programme has also developed a Consumption Cluster Diets database, which provides an overview of food consumption patterns worldwide, through 17 dietary patterns (based on population food choices) covering more than 180 countries. These estimates, together with reported contamination levels, allow assessment of the potential exposure of populations to contaminants such as aflatoxins in food. The consumption diets are based on Food Balance Sheets (FBS) data collected by the Food and Agriculture Organisation (FAO), and are routinely used by international risk assessment bodies.

                      What are the problems with the detection of presence and effects of aflatoxins and fumonisins?

                        To detect aflatoxins in food and feed, a variety of methods are available for different needs including various types of chromatography, electrophoresis, and immunosorbent assays but some of these methods are expensive and laborious. Since the distribution of moulds is not even in bulk shipments and stored grain, a proper sampling procedure is very important to ensure a representative sample and this may be a problem, especially for subsistence farmers in rural areas who do not produce enough grain to spare the quantities needed for accurate testing.

                        Detecting aflatoxins exposure or “aflatoxicosis” is difficult, both in humans and animals, due to variations in clinical signs and the presence of other factors, such as immunosuppression that can be caused by an infectious disease.

                        Of the two techniques most often used to detect levels of aflatoxins in humans, one measures a breakdown product in urine (which however is only present for 24 hours after exposure), and the other measures the level of an AFB–albumin compound present in the blood serum, providing information on exposure over weeks or months. These biomarker measurements are important in investigating outbreaks where aflatoxin contamination is suspected.

                        To detect fumonisins in maize and maize by-products, many methods have been developed, such as various types of chromatography, electrophoresis and immunosorbent assays. Some of these methods are expensive and laborious. However, studies to develop a fumonisin detection procedure that is simple, rapid, and inexpensive are ongoing. A few studies with a limited number of samples indicate that substantial amounts of bound fumonisins may be present in raw maize, but commonly used analytical methods are not able to measure their occurrence.

                        To estimate fumonisin exposure in humans, biomarkers are increasingly being used. The level of fumonisin B1 (UFB1 ) in urine is the most commonly used; it has been used to evaluate the effectiveness of dietary interventions designed to help decrease fumonisin exposure in humans. UFB1 is reflective of recent fumonisin exposure. However, in areas where maize is a dietary staple and exposure is likely to occur year-round, UFB1 levels may also be indicative of chronic exposure. Data from such areas have thus been used to verify their biochemical mechanism of action in human populations exposed daily to large amounts of fumonisin over one year.

                        How can mycotoxins be controlled in the food supply?

                          Overall, an integrated (or systemic) approach, whereby aflatoxins are controlled at all stages from the field to the table, is required for the reduction of mycotoxins contamination. Such an approach includes on the one hand pre-harvest targeted plant breeding practices, enhancement of host plant resistance and biological control methods, coupled on the other hand with post-harvest technologies such as proper drying and storage of potentially affected crop products, as well as development of appropriate alternative uses to retain at least some economic return on value of damaged crop. Both pre and post-harvest control measures are already available but more effective, sustainable and universally applicable procedures are still required.

                          Pre-harvest control measures

                          For pre-harvest control, particularly for aflatoxins, biological control is showing promise, and for fumonisins a variety of control methods are still under development including transgenic crops and diverse biological methods.

                          With the advent of new technologies such as genomics, proteomics and transcriptomics, the process of understanding and utilizing host–pathogen interactions has been significantly enhanced. Identification of markers to facilitate the transfer of resistance traits into desirable genetic backgrounds is essential for marker-assisted breeding.

                          One strategy that has received significant attention for reduction of aflatoxins prior to harvest has been biological control using non-toxigenic Aflatoxin flavus isolates. These non-toxigenic strains occupy the same niches as the naturally occurring toxigenic strains and are capable of competing and displacing the toxigenic strains. Antagonistic microorganisms have also been used.

                          The most long-term, stable solution to control pre-harvest aflatoxin contamination is nevertheless through enhancing the ability of the crop to resist fungal infection and/or prevent production of aflatoxins by the invading fungus. This can be achieved through plant breeding or through genetic engineering of crops of interest. However, these processes are laborious and time consuming.

                          As regards fumonisins, for the field, transgenic crops are being developed. For example, significantly lower levels of fumonisins have been demonstrated in Bacillus thuringiensis (Bt) modified maize, through reduction of insect pest damage and subsequent fungal infection. Other transgenic crops are being developed which would themselves detoxify mycotoxins.

                          Other methods using essential oils or specific microorganisms (lactic and propionic acid bacteria) to control fumonisins are being investigated in the laboratory. The primary method to reduce risk of fumonisins development in the field however is to implement good agricultural practice; this involves rotating crops, using hybrids or plant varieties suitable for the soil and climate, minimizing factors that increase plant stress, and implementing good soil management.

                          Action by post-harvest control measures

                          Post-harvest, aflatoxin production in storage is a potential problem in poorly stored maize whereas fumonisin is generally present initially, and their production in storage unlikely. For control of aflatoxins, interventions include measures to address adequate crops storage conditions such as moisture, temperature, mechanical or insect damage, aeration, all of which influence contamination and toxin production by mycotoxins such as aspergillus moulds.

                          To remove aflatoxins from already contaminated foodstuffs, measures, such as chemical decontamination or adsorbent clays called “enterosorbents” can be used which sequesters aflatoxins in the gastrointestinal tract and neutralizes their toxic effects by reducing the bioavailability of the toxins in the blood and other organs.

                          Reduction of fumonisin levels during sorting and cleaning depends on the initial contamination level. During the wet milling process, fumonisins are reduced in part due to the solubility of the toxins in the steep water. In dry milled products, toxin distribution is dependent on the milling strategy used. In common with other mycotoxins, the milling of cereals does not destroy fumonisins FB1, FB2 and FB3 which may occur in various cereals - primarily maize- but merely distributes them among the milling fractions or products. In general, those fractions intended for human food have reduced levels, whereas those intended for animal feed (e.g. the bran fraction) have elevated levels, which can be eliminated through a variety of processing procedures: sorting, cleaning, thermal processing (including extrusion), milling, fermentation and the traditional and commercial alkaline treatment called nixtamalization.

                          In rural settings, a number of publications have highlighted the reductions in contamination of cereal foods that can be achieved using the common processes of sorting, winnowing, washing, crushing, dehulling and fermentation (either alone or combined with steeping and cooking).

                          Anyway, further studies are required to analyse the bound fumonisins created during processing, including cooking, and to test the toxicity of bound fumonisins in animal models. So far, the few studies available on animals have shown that some processes, such as extrusion, cooking with glucose and nixtamalization, produce feeds that are less or not toxic.

                          Globally all this demonstrates that the way by which national authorities can help to control exposure and health effects of mycotoxins is through an integrative approach combining altogether the removal of the sources of contamination, promoting better agricultural and storage techniques, ensuring adequate resources are available for testing and early diagnosis, enforcing strict food safety standards, informing and educating consumers and (small/subsistence) farmers, promoting better livestock feeding and management, and creating general awareness about personal protection.

                          What can consumers do to protect themselves from mycotoxins exposure?

                            As aflatoxins and fumonisins do not always occur in the same food, WHO has developed specific recommendations on how to avoid each of these mycotoxins in the diet.

                            Aflatoxins potentially contaminate mouldy foods, which are therefore possibly harmful when consumed. The moulds do not just grow on the surface but penetrate deep into food.

                            Fumonisins will occasionally contaminate maize, and consumers living on a maize-based staple diet need to pay extra attention to minimize the risk of exposure to the toxins. Since most measures to avoid fumonisin contamination take place before harvest, the consumer has only a few opportunities to minimize the risk.

                            Therefore, to reduce exposure to mycotoxins, the consumer is advised to:

                            • buy maize, wheat and other grains and nuts as fresh as possible only from reputable brands, that have been grown as close to home as possible, and which have not been transported over a long time. Aflatoxin moulds are not entirely killed by processing or roasting, so can show up in products such as peanut butter; 
                            • before eating and/or storing, carefully inspect whole grains and nuts for evidence of mould, and discard any damaged kernels that look mouldy, discolored or shriveled moulds penetrate deep into the food and do not just grow on the surface and mouldy foods can be potentially contaminated with mycotoxins such as fumonisins. 
                            • make sure that foods are stored properly and are not kept for extended periods of time before being used; kept free of insects, dry, and not too warm. Note that maize is commonly contaminated with aflatoxins and needs to be handled properly both before and after harvest. Reduction of fumonisin levels may occur after heating but further work is still required to determine what happens to fumonisins in heated food; 
                            • try to ensure his/her diet is diverse; this not only helps to mitigate aflatoxin exposure, but also improves health and nutrition. For example, extensive aflatoxin exposure has been reported from areas where people get a major part of their daily calorie intake from maize. Consumers who lack dietary diversity need to pay extra attention to minimize the risk of high exposure to aflatoxins.  

                            What is done by WHO and national authorities to improve food safety regarding aflatoxins and fumonisins mycotoxins?

                              Exposure to aflatoxins needs to be kept as low as possible to protect the consumer. Since aflatoxins were first noted in the 1960s and fumonisins in the 1980s, they have several times been the subject of toxicological evaluations and dietary exposure assessments by the Joint FAO/WHO Expert Committee on Food Additives (JECFA). On this basis, WHO, in collaboration with FAO, evaluated the science and developed risk assessments to define safe exposure levels to mycotoxins.

                              It is based on these risk assessments that the maximum levels for aflatoxins and fumonisins in different foods are recommended by the Codex Alimentarius Commission, which mission is to create harmonized international food safety standards to protect the health of consumers, to ensure fair trade practices and further, the basis for national regulations to limit mycotoxins contamination.

                              To prevent and reduce the risk of aflatoxins in food and feed, the Codex Alimentarus Commission has also developed codes of practice, which detail appropriate preventive measures. so that consumers everywhere can be confident that the food they purchase may meet agreed standards for safety and quality, no matter where it was produced.

                              In these ways, WHO supports countries in controlling fumonisins and many have indeed now regulations governing aflatoxins in food with prescribed acceptable limits, and most have maximum permitted or acceptable levels for different foodstuffs.

                              What are the main recommendations of the Committee for reducing the risk of exposure to aflatoxins, fumonisins and their combinations?

                                The Committee recommends that efforts continue to reduce aflatoxin exposure using valid intervention strategies, including the development of effective, sustainable and universally applicable pre-harvest prevention strategies.

                                The Committee recommends in particular further research and efforts to alleviate stunting, taking aflatoxin exposure into consideration as a possible contributing factor and also that, if additional epidemiological studies are conducted, they should be prospective studies and performed in a high exposure area (e.g. in Africa).

                                More specifically, the Committee recommends among others that additional studies be conducted to better understand the occurrence of bound fumonisins in different cereals, the impact of processing on these bound mycotoxins, and their bioavailability after consumption.

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