Walter F O Marasas Wentzel C A Gelderblom Gordon S Shephard and Hester F Vismer

Abstract

The five most important naturally occurring mycotoxins in human foods and animal feeds are aflatoxin, ochratoxin, deoxynivalenol, zearalenone and fumonisin. Risk assessment is used to manage the risk from mycotoxins to protect human and animal health. Conventional risk assessment has two major components, i.e., exposure assessment and hazard assessment, which data are used to establish Maximum Tolerated Levels (MTLs). Most countries have established MTLs for total aflatoxins ranging from 4-20 ng/g. The US Food and Drug Administration (FDA) has proposed MTLs for total fumonisins of 4 ^g/g in whole maize and 2 ng/g in maize products for human consumption. The MTLs proposed by developed countries apply to commodities that they import and to foodstuffs consumed within their borders, but not to agricultural products that they export. Thus conventional risk assessment has helped manage the risk from mycotoxins in developed countries but has not helped in developing countries that import foodstuffs (or receive food aid). The situation with fumo-nisins in maize is complicated further by large differences in maize consumption by different populations, e.g., from ~5 g/person/day in Europe to ~500 g/person/day in rural Africa. The differences in maize intake have a marked effect on the Probable Daily Intake (PDI) of fumonisins by different populations. Subsistence farmers in Africa who consume homegrown maize have the highest maize intakes and also consume maize with the highest levels of fumonisin contamination. Conventional risk assessment has not been of value to them and leaves the people who are at the highest risk for mycotoxin exposure the least protected.

Introduction

Mycotoxins have undoubtedly presented a global problem to human and animal health since the earliest times, and this threat will only increase as the demand on the available food supply increases in response to the growth of the world population (Marasas and Nelson, 1987). If the food supply is limited, the mycotoxin hazard is exacerbated in at least two ways. First, more fungus-damaged, potentially mycotoxin-containing foodstuffs are consumed rather than discarded, and second, malnutrition enhances the susceptibility to lower levels of foodborne mycotoxins.

© CAB International 2008. Mycotoxins: Detection Methods, Management, Public Health - 29 -and Agricultural Trade (eds. J. F. Leslie et al.).

Natural outbreaks of mycotoxicoses occur world-wide, from the humid tropics to Siberia. Although the climate in a particular country may not favor the elaboration of a specific mycotoxin, such as aflatoxin, the problem may be imported from another country in the form of agricultural products, such as peanuts or maize.

Mycotoxins affect both animals and humans acutely as well as chronically. Acute outbreaks of mycotoxicoses are the tip of the iceberg, whereas chronic effects, such as growth stunting, immune suppression and cancer, are much more important although they may not be as evident. A problem cannot be controlled before it is recognized, and acceptance by governments of developed and developing countries that mycotoxins represent a serious health hazard in addition to serving as a trade barrier with significant economic impacts, is a matter of urgency. Mycotoxins are a global problem that requires a global solution to prevent or reduce the development of mycotoxigenic fungi, their insect vectors and the resulting mycotoxin contamination of agricultural crops in the field and in storage. The extent of the mycotoxin problem, particularly with respect to the foodborne carcinogenic mycotoxins, aflatoxin and fumonisin, risk assessment and possible solutions are discussed in this chapter.

Mycotoxigenic Fungi, Mycotoxins and Mycotoxicoses

Globally, the five most important mycotoxin-producing fungi are (Miller, 2002): Aspergillus flavus, Aspergillus ochraceus, Penicillium verrucosum, Fusarium graminearum and Fusarium verticillioides. The five most important mycotoxins that occur naturally in agricultural products are (Miller, 1995): aflatoxin produced by A. flavus; ochratoxin produced by A. ochraceus and P. verrucosum; deoxynivalenol and zearalenone produced by F. gra-minearum; and fumonisin produced by F. verticillioides. Human diseases that have been associated with two of these mycotoxins in foods are: acute toxic hepatitis and liver cancer with aflatoxin; and esophageal cancer and neural tube defects with fumonisin.

Aflatoxins

Aflatoxins are carcinogenic mycotoxins produced by some Aspergillus species in a wide range of agricultural commodities, primarily by A. flavus in maize and peanuts. Aflatoxin Bi was first identified in the United Kingdom in 1960 in a shipment of peanuts from Brazil. Subsequently, aflatoxin B1 was shown to cause outbreaks of acute hepatitis in animals and humans, to cause liver cancer in animals, and to be associated with liver cancer in humans, particularly in combination with hepatitis B virus infection in sub-Saharan Africa and Southeast Asia (Turner et al., 2002). The International Agency for Research on Cancer (IARC) evaluated aflatoxin B1 as a Group 1 carcinogen, i.e., carcinogenic to humans (IARC, 1993). Maximum tolerated levels of aflatoxins in foods and feeds are regulated in most countries world-wide and commonly range from 4-20 ng/g (FAO, 2004). The danger of consuming foodstuffs contaminated with aflatoxin at levels above the regulatory limit was again demonstrated in 2004 in Kenya where 125 people died following the consumption of homegrown maize containing high levels of aflatoxin (Lewis et al., 2005).

Fumonisins

Fumonisins are carcinogenic mycotoxins produced by some Fusarium species, primarily F. verticillioides growing in maize. Fumonisins were first isolated and identified in South Africa in 1988 from cultures of Fusarium verticillioides (= F. moniliforme) strain MRC 826 (Gelderblom et al., 1988). During 1989/1990, broken maize kernels (screenings) from the 1989 maize crop in the United States caused widespread outbreaks of leukoencephalo-malacia (LEM) in horses and pulmonary edema syndrome in pigs throughout the country. By 1990 both of these syndromes were proven to be caused by fumonisin Bi (Marasas, 2001). Analytical methods for the detection of fumonisin B1 and fumonisin B2 in maize also were developed in 1990 (Shephard et al., 1990). Reports followed of naturally occurring levels of the toxin in maize screenings associated with field outbreaks of leukoencephalo-malacia and pulmonary edema syndrome as well as in home-grown maize in high-incidence areas of human esophageal cancer in the Transkei region of South Africa (Rheeder et al., 1992) and China (Chu and Li, 1994). During 1991, fumonisin B1 was shown to cause liver cancer in rats (Gelderblom et al., 1991). The carcinogenicity of fumonisin B1 was confirmed by the National Toxicology Program (NTP) of the United States Food and Drug Administration (FDA) in a two-year feeding study in rats and mice (Howard et al., 2001). The Joint FAO/WHO Expert Committee on Food Additives (JECFA) evaluated the fumonisins and allocated a group provisional maximum tolerable daily intake (PMTDI) of 2 ^g/kg body weight to fumonisin B1, fumonisin B2 and fumonisin B3, alone or in combination (WHO, 2002). The IARC evaluated fumonisin B1 as a Group 2B carcinogen, i.e., possibly carcinogenic to humans (IARC, 2002). Although the role of fumonisin B1 in esopha-geal cancer has not been proven, fumonisin has to be considered as a risk factor, particularly in rural populations living on a maize-based staple diet.

Fumonisin B1 is known to inhibit folic acid transport by the folate receptor and because folic acid deficiency causes neural tube defects, some birth defects in humans may be caused by dietary exposure to fumonisin B1 (Hendricks, 1999). Fumonisin B1 causes cranial neural tube defects in mouse embryos and folic acid prevents fumonisin B1-induced neural tube defects in these animals (Sadler et al., 2002; Gelineau-van Waes et al., 2005). The high-incidence areas of esophageal cancer in South Africa and China, where high levels of fumo-nisin in the maize staple diet have been reported, also are high incidence areas for neural tube defects in humans (Marasas et al., 2004). The possible role of fumonisin as a cause of birth defects in high incidence areas of Africa, Asia and South America requires further investigation.

At least 28 fumonisin analogs are now known (Rheeder et al., 2002) and three of these (fumonisin B1, fumonisin B2 and fumonisin B3) occur naturally in maize world-wide, sometimes at very high levels of up to 330 ^g/g (Shephard et al., 1996). Fumonisins and aflatox-ins often co-occur in maize and a synergistic interaction between fumonisin B1 and aflatox-in B1 is known (Gelderblom et al., 2002).

The FDA has published a "Guidance for Industry" (FDA, 2001) with respect to fumonisin levels in human foods and animal feeds that the FDA considers to be adequate to protect human and animal health. These levels range from 2-4 ^g/g in maize intended for human consumption and 1-50 ^g/g in animal feeds. However, the risk of fumonisin contamination of maize to the consumer is determined by both maize intake and level of contamination (Table 1). In general, the highest maize consumers in rural areas also consume the most highly contaminated home-grown maize (Gelderblom et al., 1996; Marasas, 1997).

Table 1. Interactive associations between fumonisin contamination (pg/g maize) and maize intake profiles (g/60 kg person/day) shown as Probable Daily Intake (PDI; pg/kg body weight/day). Provisional Maximum Tolerable Daily Intake (PMTDI) calculations are based on nephrotoxic effects as set forward by the JECFA (WHO, 2002) or hepatocarcinogenic effects as proposed by Gelderblom et al. (1996).

White areas: PMTDI falls within the tolerable daily intake level; lightly shaded areas: PMTDI = 0.8 pg/kg body weight/day (hepatocarcinogenicity); medium shaded areas: PMTDI between 0.8 and 2 pg/kg body weight/day (nephrotoxicity); dark shaded areas: PMTDI values above the maximum tolerable daily intake levels.

White areas: PMTDI falls within the tolerable daily intake level; lightly shaded areas: PMTDI = 0.8 pg/kg body weight/day (hepatocarcinogenicity); medium shaded areas: PMTDI between 0.8 and 2 pg/kg body weight/day (nephrotoxicity); dark shaded areas: PMTDI values above the maximum tolerable daily intake levels.

Such maize is not subject to national or international regulations based on the MTLs of af-latoxin or the guidelines proposed for fumonisin by the FDA.

Economic Impacts of Mycotoxins

Few attempts to estimate the economic costs of mycotoxins in monetary terms have been published. Lubulwa and Davies (1995) estimated the social costs of the impacts of fungi and aflatoxins in maize and peanuts in Indonesia, Philippines and Thailand during 1991 to be Aus.$ 477 million. The economic models used to make this estimate included the evaluation of product spoilage effects, human health effects with respect to disability and premature death due to aflatoxin-related primary liver cancer and livestock health effects due to reduced feed efficiency and increased mortality. The estimate, however, did not include the costs associated with immune suppression and growth stunting (see Chapters 5 and 6) or those from the loss of export markets for the contaminated commodities.

The effects of regulating mycotoxin levels on trade in agricultural products have been investigated by the World Bank (Otsuki et al., 2001a,b). The implementation of a new European Union (EU) aflatoxin standard which is lower (4 ng/g aflatoxin Bj) than the internationally accepted Codex Alimentarius standard would reduce health risks by 2.3 deaths per billion people per year, but with a reduction of 64% in the export of cereals and peanuts from Africa to Europe at a cost of US$ 670 million (Otsuki et al., 2001b). In a subsequent World Bank study by Jaffee and Henson (2004) these findings were challenged because the estimated "cost" of US$ 670 million had been misinterpreted as actual losses of trade rather than an estimate from an econometric simulation. Jaffee and Henson (2004) concluded that

EU imports from Africa would increase due to the more stringent aflatoxin standards, whereas some competing countries, e.g. Turkey, incurred more rejections. Similarly, Wu (2004a) stated that the developing countries most likely to experience large losses from the tighter mycotoxin standards are not sub-Saharan African nations, but China and Argentina. Among developed countries the United States would experience the heaviest economic losses. The three largest maize exporting countries are the United States, China and Argentina. Wu (2004a) calculated that if the current FDA guideline of 2 ^g/g fumonisin were adopted internationally, then the export losses to each of these three countries would range from US$ 20-40 million annually with a total loss amongst the three countries of US$ 100 million. A fumonisin standard of 0.5 ^g/g would increase the maize export losses to the United States to US$ 170 million, to China to US$ 60 million, and to Argentina to US$ 70 million, for a total of US$ 300 million.

The potential annual cost of contamination of food and feed crops in the United States with three mycotoxins (aflatoxin, fumonisin and deoxynivalenol) is estimated to range from US$ 418 million to US$ 1.66 billion, with a mean estimated cost of US$ 946 million (CAST, 2003). In addition, the costs of mycotoxin management, including research and monitoring, are estimated at between US$ 500 million and US$ 1.5 billion (Robens and Cardwell, 2003).

Risk Assessment and Regulation of Mycotoxins

Conventional risk assessment of mycotoxins has two major components, i.e., exposure assessment and hazard assessment (Gelderblom et al., 1996; Marasas, 1997). Exposure is calculated from food intake and naturally occurring levels of a mycotoxin and expressed as the Probable Daily Intake (PDI). Hazard is calculated from toxicological studies in experimental animals and is expressed as the Tolerable Daily Intake (TDI). The PDI and TDI data are used to assess the risk of a mycotoxin and establish MTLs.

Risk assessment of fumonisins to human health has been performed (IARC, 2002; WHO, 2002) and MTLs proposed ranging from 100-200 ng/g (Gelderblom et al., 1996, Marasas, 1997), to 2-4 ^g/g (FDA, 2001). It remains to be seen if and when the fumonisin levels proposed in the FDA Guidance for Industry (FDA, 2001) will be implemented. Vil-joen and Marasas (2003) supported the fumonisin levels proposed by the FDA and pointed out that lower MTLs could seriously limit the food supply and affect the entire grain chain from producer to consumer.

Conventional risk assessment and MTLs do not apply to subsistence farmers in Africa who consume the largest amounts of maize containing the highest levels of fumonisins due to the interaction between maize intake and fumonisin contamination (Table 1). The intake profiles for the best quality maize with the lowest fumonisin contamination levels provide PDI values well below the PMTDI of 2.0 ^g/kg bw/day proposed by the JECFA (WHO, 2002). This scenario reflects the typical situation in developed countries where maize consumption is low and mycotoxin contamination of foodstuffs is strictly regulated. In contrast, a completely different situation prevails in developing countries, particularly in rural and subsistence farming communities, where home-grown maize is the major dietary staple. High fumonisin contamination levels together with high maize consumption patterns (400-500 g/person/day) result in PDI values well above (10-50 fold higher) the PMTDI. The risk of developing disease due to fumonisin intake is further increased when consider ing the maize consumption patterns in children. Detailed maize intake profiles in different population groups, particularly in Southern and Eastern Africa where maize is the staple diet, are required to accurately assess the risk of fumonisins to human health. The implementation of MTLs based on conventional risk assessment in developed countries to protect the health of the lowest maize consumers may make the situation worse as food security problems will lead the highest consumers in the producing countries to consume the contaminated maize rejected by the importing countries. A similar rationale applies to MTLs for afla-toxin in peanuts.

People in rural areas of developing countries, who are at the highest risk from mycotox-ins in staple foods, particularly subsistence farmers, are completely unprotected by mycotoxin regulations. Moreover, in developing countries in Africa and elsewhere, food safety is an issue that frequently must be balanced against issues of food security (Shephard, 2003). Given the choice between starvation and consuming foods containing mycotoxins at levels higher than the prescribed MTLs, most people in developing countries would probably eat the foodstuffs that would be rejected by developed countries. Thus, people who are at the highest risk, also have the most urgent need for solutions other than regulation for the mycotoxin problem.

Possible Solutions

The ultimate solution to the global mycotoxin problem is not regulation, but reduction of fungal infection and mycotoxin levels in crop plants (Marasas and Nelson, 1987; WHO, 2000). Attempts to achieve this goal by conventional plant breeding have not been very successful for various reasons including the lack of major single genes and difficulties in selecting appropriate germplasm due to time-consuming and expensive mycotoxin analyses (Gressel et al., 2004; Munkvold, 2003). Although several sources of resistance to A. flavus infection and/or aflatoxin production in maize have been identified, the levels of genetic resistance are not sufficient to prevent the development of unacceptable aflatoxin levels. The same problem also occurs with the polygenic sources of resistance to F. verticillioides and fumonisin levels in maize (Munkvold, 2003). Molecular markers are being used increasingly to facilitate selection and to combine resistance genes from different sources in order to develop varieties with high yields and low mycotoxin levels, but potentially commercial lines have yet to be identified.

The most promising approach for innovative solutions is biotechnology. Genetic engineering approaches are the most attractive methods now under development, and the future of fumonisin reduction may lie in the hands of biotechnologists. The potential of transgenic resistance to mycotoxigenic fungi and/or their mycotoxins as biotechnology solutions for the global mycotoxin problem is receiving intensive international attention. The following strategies that might be used to reduce fumonisins in maize were reviewed by Duvick (2001).

Reducing infection by the mycotoxigenic fungus

Several antifungal compounds in plants are potential candidates for genetic engineering to alter maize genotypes for resistance to mycotoxigenic fungi.

Inserting genes capable of degrading the mycotoxin

Progress has been made with this strategy of in planta detoxification of fumonisins in maize. Duvick (2001) reported that two species of saprophytic fungi (Exophiala spinifera and Rhi-nocladiella atrovirens) from moldy maize ears can utilize FBj as their sole carbon source. These fungi produce enzymes capable of hydrolyzing and further metabolizing fumonisins by oxidative deamination. The genes coding the specific enzymes that carry out the detoxification steps have been cloned and the effects of the expression of these genes in trans-genic maize on fumonisin levels are currently being evaluated in the United States (Duvick, 2001).

Interfering with mycotoxin biosynthesis

An a-amylase inhibitor has been identified in the legume Lablab purpureus that inhibits aflatox-in biosynthesis (Munkvold, 2003). This gene is a candidate for expression in genetically modified crops to reduce aflatoxin contamination. Genes that regulate fumonisin production by F. verticillioides have been identified (Proctor et al., 2003; Brown et al., 2005) and this information has the potential to be used in transgenic maize to disrupt fumonisin biosynthesis.

Inserting genes for insect resistance

There is a close association between insects, e.g., the European corn borer (Ostrinia nubila-lis), and the infection of maize by F. verticillioides, so transgenic maize hybrids carrying genes encoding insecticidal proteins from Bacillus thuringiensis (Bt) are a potential solution to the fumonisin problem. Bt hybrids, which are resistant to the European corn borer and have correspondingly less F. verticillioides ear rot, had significantly lower fumonisin levels than did conventional hybrids grown in Iowa, USA (Munkvold et al., 1999). Similar results were subsequently reported for Bt hybrids elsewhere in the world where fumonisin contamination of maize is associated with insect damage such as France, Italy and Spain (Munkvold, 2003). Bt hybrids represented approximately 25% of the field maize planted in the United States and the estimated annual saving to farmers due to reduced mycotoxin (fumonisin and deoxynivalenol) levels alone, is US$ 17 million (Wu et al., 2004). Whether currently available Bt hybrids also contain significantly less fumonisin than non-Bt hybrids in countries where other species of corn borers predominate, e.g., Busseola fusca in West Africa (Cardwell et al., 2000) and South Africa (Flett and van Rensburg, 1992), remains unknown. In South Africa, significant reductions in fumonisin levels have been found in some Bt culti-vars in some seasons in some locations (Vismer et al., 2005). If additional Bt genes are deployed to control a broader range of maize insects, then the reduction in fumonisin levels may be improved further.

Conclusions

The EU continues to make mycotoxin standards more stringent by lowering the MTL in imported agricultural products on the one hand, while prohibiting the importation of GM crops on the other. This impasse is a serious obstacle to the implementation of biotechnolo gy solutions to the mycotoxin problems of exporting countries. The reasons why decision makers at both the government and individual consumer levels have not endorsed Bt maize and other GM crops are complex (Wu, 20046). The potential benefits of Bt maize, e.g., increased yield, decreased use of pesticides and reduced mycotoxin levels, should be emphasized in educational programs to improve public understanding of biotechnology by providing accurate and balanced information.

During the Workshop on Mycotoxins in Food in Africa (Cardwell, 1996; Cardwell and Miller, 1996) held in Cotonou, Benin, 6-10 November 1995 it was resolved by an international, multidisciplinary team of scientists that:

Recognizing the increasing importance of food grains in sub-Saharan Africa; Realizing that heavy losses are caused by mycotoxins at all levels of production, storage, processing, and utilization; and being

Concerned that mycotoxins are having a direct negative impact on human and animal health, and on trade; and being

Aware that African governments are fully committed to the promotion of food security and safety, and to the improvement of public health and quality of life for their citizenry Be it Resolved that The Pan African Mycotoxins Initiative Committee: Does Hereby Reiterate that appropriate measures must be taken to reduce the grain losses caused by mycotoxins to internationally accepted standards, and to increase production of good quality grains; and

Advocates that resources be mobilized by African governments and the international community for support to mycotoxin research and intervention initiatives. We strongly recommended that not only governments of African countries, but that governments of all developed and developing countries support the search for, as well as the development and implementation of, solutions for the global mycotoxin problem.

Acknowledgements

We thank all of our colleagues, past and present, at the PROMEC Unit of the South African Medical Research Council (MRC) for their invaluable contributions to the global knowledge of mycotoxins, and the MRC for continuous funding from 1975 to the present.

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