Mycotoxin contamination of the feed supply chain: Implications for animal productivity and feed security

Animal Feed Science and Technology 173 (2012) 134–158

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Mycotoxin contamination of the feed supply chain: Implications for animal productivity and feed security夽 Wayne L. Bryden ∗ The University of Queensland, School of Agriculture and Food Sciences, Gatton, Queensland 4343, Australia

a r t i c l e

i n f o

Keywords: Mycotoxin Mycotoxicoses Fungi Pigs Poultry Feed supply chain Feed security

a b s t r a c t Fungi are ubiquitous and formation of mycotoxins can occur in all agricultural commodities under appropriate field or storage conditions throughout the animal feed supply chain. In this increasingly complex area, the salient features of a fungal growth and mycotoxin production are outlined with strategies to mitigate their accumulation. Overall, there are a number of approaches that can be taken to minimise mycotoxin contamination in animal feeds and these involve prevention of fungal growth and therefore mycotoxin formation, and strategies to reduce or eliminate mycotoxins from contaminated commodities, especially feed additives. The major problem associated with mycotoxin contaminated animal feed is not acute disease episodes but low level toxin ingestion which may cause an array of metabolic disturbances resulting in poor animal productivity. In studies with pigs and poultry it has been shown that low level mycotoxin intake can result in reduced feed intake, poor growth rate, lower egg production, changes in carcass quality, reduced fertility and hatchability of eggs and immunosuppression. It is concluded that mycotoxins constitute a significant problem for the animal feed industry and an ongoing risk to feed supply security. © 2011 Elsevier B.V. All rights reserved.

1. Introduction Feed supply is central to all animal production systems and any factor that affects the security of the feed supply is a significant constraint to production. Feed spoilage by fungi can be a problem for feed security. It may result in heating and mustiness, reduced palatability and the loss of nutritive value (Christensen, 1974). In addition, the affected commodity may become contaminated with toxic secondary fungal metabolites known as mycotoxins. The syndromes resulting from the ingestion of these fungal compounds are mycotoxicoses (Richard, 2007). The biological reactions following ingestion of one or a combination of mycotoxins vary from acute, overt disease with high morbidity and death to chronic, insidious disorders with reduced animal productivity. Fortunately, mycotoxin contamination levels in animal feedstuffs are usually not high enough to cause an overt disease but may result in economical loss through clinically obscure changes in growth, production and immunosuppression (Hamilton, 1982). These insidious effects of mycotoxin exposure are the focus of this review. Globally, mycotoxins have significant human and animal health, economic and international trade implications (Wu, 2004; Bryden, 2007; Wild, 2007; Wild and Gong, 2010). The supply of meat, milk and eggs, the human food products

Abbreviations: AME, apparent metabolisable energy; CAST, Council for Agricultural Science and Technology; CPA, cyclopiazonic acid; DON, deoxynivalenol; ELISA, enzyme-linked immunosorbent assays; FAO, Food and Agriculture Organization of the United Nations; HACCP, hazard analysis critical control points; HSCAS, hydrated sodium calcium aluminosilicate; JEFCA, Joint FAO/WHO Expert Committee on Food Additives; NTD, neural tube defects. 夽 This paper is part of the special issue entitled Nutrition and Pathology of Non-Ruminants, Guest Edited by V. Ravindran. ∗ Tel.: +61 7 5460 1250; fax: +61 7 5460 1444. E-mail address: [email protected] 0377-8401/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.anifeedsci.2011.12.014

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Table 1 Toxigenic fungi and associated mycotoxins. Fungal species

Mycotoxin

Aspergillus flavus; A. parasiticus A. flavus A. ochraceus; A. carbonarius; Penicillium verrucosum P. citrinum; P. expansum Fusarium sporotrichioides; F. poae F. sporotrichioides; F. poae F. culmorum; F. graminearum F. culmorum; F. graminearum F. verticillioides; F. proliferatum Alternaria alternata Claviceps purpurea

Aflatoxins Cyclopiazonic acid Ochratoxin A Citrinin T-2 toxin Diacetoxyscirpenol Deoxynivalenol Zearalenone Fumonisins Tenuazonic acid Ergot alkaloids

of animal production, can be adversely affected by mycotoxins. This has significant consequences in both developed and developing countries. In developing countries the primary concern with mycotoxin contamination of the food supply chain is human health (Miller, 1998; Shier et al., 2005; Wild, 2007; Shephard, 2008) and the impact on animal health and production is the second major concern (Shier et al., 2005). Whereas in developed economies, where mycotoxin contamination in the food and feed chains is tightly regulated to reduce human and animal exposure, the additional costs to the producer and/or the consumer to meet the economic burden of regulating the food and feed supply is the major mycotoxin concern. This is followed by the impact on animal health and production (Shier et al., 2005). Those developing regulations for the risk management of mycotoxins seek to balance the need to protect human health with economic concerns and in so doing go through a very detailed risk assessment process (see Kuiper-Goodman, 2004). Fungi are ubiquitous and all feedstuffs can be contaminated with mycotoxins. Formation of mycotoxins is not restricted to any component of the animal feed supply chain but the level of contamination varies with location and reflects different agronomic practices and climatic conditions, which dictate the fungi that are present in a farming system (Wicklow, 1995; Bryden, 2009) and are outlined in this review. Moreover, as feed is the major cost of intensive animal production, any threat to feed security can have a significant impact on the economic viability of the intensive animal industries. Within this context, the salient features of a number of mycotoxicoses of poultry and pigs are described and where appropriate, equine and ruminant examples are included. The implications for animal productivity are discussed and the difficulties of diagnosing mycotoxicoses are outlined along with strategies to mitigate mycotoxin contamination of feedstuffs. It is concluded that mycotoxins constitute a significant problem for the animal feed industry and an ongoing risk to the security of the feed supply. 2. Fungal ecology and mycotoxin occurrence The fungal species most often encountered with intoxications belong primarily to five genera: Alternaria, Aspergillus, Cladosporium, Fusarium, and Penicillium. Other genera including Chaetomium, Claviceps, Diplodia, Myrothecium, Phoma, Phomopsis, Pithomyces and Strachybotrys also contain mycotoxic fungi (Moss, 1991). These moulds produce many different toxic compounds but not all isolates of the same species produce toxins (Cole et al., 2003; Brase et al., 2009). The genera of most concern globally are Aspergillus, Fusarium and Penicillium (Miller, 1998). The major toxins produced by these three genera include: aflatoxins, ochratoxins, trichothecenes, fumonisins and zearalenone (Miller, 1998). The ergot alkaloids produced by Claviceps and Neotyphodium (Bryden, 1994) and toxins produced by Alternaria (Ostry, 2008) also cause disease-related problems from time to time. The common toxigenic fungi and associated mycotoxins are shown in Table 1. As depicted in Fig. 1 and discussed below, fungi can elaborate mycotoxins in all segments of the animal feed supply chain. 2.1. Conditions favouring mycotoxin production Fungi are a normal part of the microflora of standing crops and stored feeds, but the production of mycotoxins depends upon the fungi present, agronomic practices, the composition of the commodity and the conditions of harvesting, handling and storage (Bryden, 2009). The amount of toxin produced will depend on physical factors (moisture, relative humidity, temperature and mechanical damage), chemical factors (carbon dioxide, oxygen, composition of substrate, pesticide and fungicides), and biological factors (plant variety, stress, insects, spore load) (Frisvad, 1995; Wicklow, 1995). Moisture and temperature have a major influence on mould growth and mycotoxin production. Although water activity is the most useful expression of the availability of water for microorganism growth (Pitt and Hocking, 1997), it is convenient to express the water content of a feed commodity as moisture percentage. Pathogenic fungi that invade crops prior to harvest usually require higher moisture levels (200–250 g/kg) for infection than fungi that can proliferate during storage (130–180 g/kg). Therefore most feedstuffs with moisture contents above 130 g/kg are susceptible to mould growth and mycotoxin formation. Importantly, toxin production is often unrelated to total fungal biomass and the ecological requirements for growth and mycotoxin production may differ considerably between fungal species (Magan, 2006).

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Fig. 1. Factors affecting mycotoxin occurrence in the human food and animal feed chains. (adapted from Pestka and Casale, 1990)

2.2. Mycotoxin production pre- and post-harvest The accumulation of mycotoxins both before and after harvest (see Table 2) largely reflects climatic conditions. Fusarium toxins are produced in cereal grains during high moisture conditions around harvest (Sutton, 1982; Munkvold and Desjardins, 1997), whereas pre-harvest aflatoxin contamination of crops, including peanuts (Diener et al., 1987; Dorner et al., 1989; Dorner, 2008) and maize (Payne, 1998), is associated with high temperatures, insect damage and prolonged drought conditions. The relationships between planting date, drought stress, and insects with fumonisin contamination of maize are complex (Parsons and Munkvold, 2010). Moreover, because Aspergillus can tolerate lower water activity than Fusarium, it is more likely to contaminate commodities both pre- and post-harvest whereas Fusarium is more likely to be found as a contaminant pre-harvest (Abramson, 1998). These examples demonstrate that although it may be convenient to describe fungi as either pre- and post-harvest organisms, the actual colonisation and proliferation of fungi is not clear cut but depends on the environmental and ecological circumstances and the resulting toxins will differ accordingly. Stored grain is not static; it is in a dynamic state and may become infested with fungi and insects. These interrelationships are affected by climatic factors such as temperature and humidity, by geographical location, by the type of storage container

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Table 2 The most commonly associated mycotoxins with cereal grains following pre- or post-harvest contamination. Some mycotoxins can be produced both preand post-harvest depending on climatic conditions. Cereals

Pre-harvest

Post-harvest

Barley Maize Oats Rice Rye Sorghum Wheat

DON, NIV, Zea, HT-2, T-2 DON, Fum, Zea, DON, NIV, HT-2, T-2

OTA, Afla, Cit Zea, Afla, OTA, Cit Afla, Sterig, OTA OTA Afla OTA, Afla, Cit

Ergot Ergot DON, NIV, Zea, ergot

(adapted from Petterrson, 2004) Note: Afla = aflatoxins; Cit = citrinin; DON = deoxynivalenol; Sterig = sterigmatocystin; Zea = zearalenone.

Ergot = ergotamine;

HT-2 = HT-2

toxin;

NIV = nivalenol;

OTA = ochratoxin

A;

and by grain handling and transport (Christensen, 1974; Chelkowski, 1991; Jayas et al., 1995). Moisture depends mostly on water content at harvest, the amount of drying, aerating, and turning of the grain before or during storage as well as the respiration of insects and microorganisms in the stored grain. Magan et al. (2010) have recently reviewed the strategies that need to be implemented to limit mycotoxin accumulation post-harvest. Provided grain is dry when placed in storage, moisture content can only rise from leaks or condensation. Grain may go into storage at a uniform temperature but over a period the grain mass will cool at a different rate in the centre than at the periphery. As a result of temperature differentials moisture migrates through the storage bin, resulting in condensation and the provision of ideal conditions for mould growth or the development of ‘hot spots’ in localised areas (Wicklow, 1995). Microbial and insect growth in stored grain also results in moisture condensation and the potential development of ‘hot spots’. The minimum critical levels for the growth of fungi are 70–150 g/kg moisture (depending on commodity) and 80–85% relative humidity. Temperatures at which toxin production can take place vary from 0 ◦ C to 35 ◦ C, depending on fungal species (Frisvad, 1995; Wicklow, 1995). 2.3. Mycotoxin contamination of feedstuffs Most mycotoxins are very stable chemically and once formed in a feedstuff will continue to contaminate that commodity and feeds manufactured from it. Extensive surveys have been published on the occurrence of mycotoxins, including those by Scott (1978), Smith and Henderson (1991), Filtenborg et al. (1996), Meister and Springer (2004), Binder et al. (2007), Trucksess and Scott (2008) and Reddy et al. (2009). Of the five major classes of mycotoxins, the trichothecenes, fumonisins and zearalenone are invariably found in cereal grains. Aflatoxin and ochratoxin can be found in a wide range of feed commodities pre-harvest; this will depend on regional differences and prevailing climatic conditions. Significant quantities of aflatoxin can be found in maize, peanuts and tree nuts (Reddy et al., 2009). Wheat, rye, barley and grapes can be contaminated with ochratoxin (Jørgensen, 2005). The fungi that produce these toxins also produce other toxins and in many situations co-contamination may occur. This is exemplified by Fusarium species (Desjardins, 2006; Glenn, 2007) and summarised in Table 3. Binder et al. (2007) have completed a global survey of the incidence of mycotoxins (aflatoxin B1, DON, fumonisins B1, B2 and B3, ochratoxin A, T-2 toxin and zearalenone) in animal feedstuffs. They found low level contamination throughout the world with significant regional differences, especially between tropical and temperate areas. European samples had DON, T-2 toxin and zearalenone as major contaminants while aflatoxins, DON, fumonisins and zearalenone tended to contaminate samples from Asia and the Pacific. This group has undertaken a similar global survey each year since 2005 in which about 3000 samples have been analysed (Rodrigues and Griessler, 2010; Rodrigues and Naehrer, 2011). A similar regional pattern of contamination is apparent each year. The levels of mycotoxins detected were generally below those considered harmful to farm animals but significantly approximately half the samples contained more than one toxin. It is difficult from surveys Table 3 Some mycotoxigenic Fusarium species and the mycotoxins they produce.a Species

Mycotoxin

F. acuminatum F. armeniacum F. crookwellense F. culmorum

Acuminatum, aurofusarin, beauvericin, chlamydosporol, enniatins, fusarins, moniliformin, trichothecenes Beauvericin, fusarins, trichothecenes Aurofusarin, butenolide, culmorin, cyclonerodiol, fusaric acid, fusarins, trichothecenes, zearalenone Aurofusarin, butenolide, chlamydosporol, culmorin, cyclonerodiol, cyclonerotriol, fusarins, moniliformin, trichothecenes, zearalenone Beauvericin, equisetin, fusarochromanone, moniliformin, trichothecenes, zearalenone Aurofusarin, butenolide, chlamydosporol, culmorin, cyclonerodiol, fusarins, trichothecenes, zearalenone Beauvericin, enniatins, fumonisins, fusaric acid, fusaproliferin, moniliformin Trichothecenes, zearalenone Aurofusarin, beauvericin, butenolide, culmorin, enniatins, fusarins, moniliformin, trichothecenes Fumonisins, fusaric acid, fusarins, naphthoquinones

F. equiseti F. graminearum F. proliferatum F. pseudograminearum F. sporotrichioides F. verticillioides a

Adapted from Desjardins (2006).

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Table 4 Low level feed contamination with aflatoxin and broiler performance.a Parameter

Normal mill

Problem mill

Frequency of aflatoxin B1 (%) Range (␮g/kg) Feed conversion ratio Body weight (kg)

2 0–6 2.00 2.04

30 0–30 2.02 2.00

a

Adapted from Hamilton (1978).

of this nature to draw conclusions regarding the significance of the results to on farm animal productivity, except continual vigilance for the likely occurrence of mycotoxins. Obviously the simultaneous exposure of animals and poultry to more than one toxin is of concern and requires more study (Speijers and Speijers, 2004). This is exemplified by a recent report (Stoev et al., 2010) which concludes that mycotoxic nephropathy in Bulgarian pigs and chickens has a multi-toxin aetiology involving ochratoxin A, penicillic acid, fumonisin B1 and an uncharacterised metabolite. Many factors contribute to feed contamination with mycotoxins and subsequent animal exposure. Two important factors, discussed below, are genetic modification of crops to resist fungal attack and feed handling on farm. 2.3.1. Genetically modified crops Fungal geneticists have unravelled the pathways and the genes responsible for the synthesis and regulation of mycotoxin production, especially aflatoxin and the trichothecenes (Yu and Keller, 2005; Bhatnagar et al., 2008) and this may assist in the development of plants that are resistant to toxin accumulation. In some respects, this is demonstrated by the success of Bt maize hybrids which have been developed as a means of transgenic insect protection (Wu et al., 2004). The transgenic Bt corn or maize contains a gene from the soil bacterium Bacillus thuringiensis which encodes for a protein that is toxic to common lepidopteran maize pests. These hybrids offer a new tool for mycotoxin management because insect damage is often a major aetiological factor in facilitating toxigenic fungal infection of crops (Dowd, 1998). Bt maize is effective in reducing the incidence of fumonisin contamination but less effective in reducing deoxynivalenol contamination (Munkvold, 2003). This reflects different disease patterns and pathogens as deoxynivalenol is associated with Gibberella ear rot whereas fumonisin production is associated with Fusarium ear rot and the occurrence of Gibberella ear rot is not as strongly influenced by insect damage as is fumonisin accumulation (Munkvold and Desjardins, 1997). Aflatoxin contamination of maize has not been consistently reduced in Bt hybrids compared with non Bt hybrids (Munkvold, 2003). Aflatoxin accumulation is influenced by insect injury to the plant but this is probably overridden by drought and high temperatures which explains the inconsistent results that have been found with aflatoxin accumulation and the use of Bt maize. 2.3.2. On farm contamination Incorrect bulk handling and inferior storage conditions can have a major influence on the degree of contamination of feedstuffs, as indicated above. Farm feed storage and on farm feeding systems can also contribute to mycotoxin exposure of the animals being fed. In a series of studies, Hamilton and his colleagues (see Hamilton, 1978, 1985) were able to demonstrate that levels of aflatoxin that did not appear to effect broiler health, did impact negatively on bird performance. As shown in Table 4, the difference in aflatoxin contamination of the feed obtained from either a “normal” or “problem” feed mill was very small but economically significant when fed to large broiler flocks (Hamilton, 1978). In another study by this group (Smith and Hamilton, 1970), the frequency of aflatoxin contamination of feed being consumed by chickens was 91% compared to 52% in newly manufactured feed. Thus as is evident in Table 5, aflatoxin formation can occur before, during and after feed manufacture. Importantly, it has been demonstrated that simple measures can significantly reduce the risk of mycotoxin exposure on farm. Storage of grain at appropriate moisture content (below 130 g/kg), inspection of grain regularly for temperature, insects and wet spots will limit the possibility of fungal development in feeds and feedstuffs as discussed above. The risk of feed contamination will be reduced in animal units with rapid turnover of feed because there will be less time for fungal growth and toxin production. Good and Hamilton (1981) demonstrated that increasing feed turnover or decreasing feed Table 5 Survey of feed and ingredients for aflatoxin during an outbreak of aflatoxicosis in chickens. Material

Aflatoxin frequencya (%)

Soybean meal Maize Other ingredients Feed from mill Feed in feed trough

5 30 0 52 91

(adapted from Hamilton, 1985) a Frequency is percentage of samples of each material that contained aflatoxin.

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Table 6 Mycotoxin concentrations in samples of grains, forages and straw.a Mycotoxin

Feedstuff

No. of samples

Positive (%)

Aflatoxin B1

Grains Forages Straw

49 33 56

14 39 23

9 10 9

17 16 11

Zearalenone

Grains Forages Straw

45 33 56

22 67 52

147 1058 556

258 5811 3551

Deoxynivalenol

Grains Forages Straw

45 33 56

9 45 52

961 477 461

3000 1758 1860

a

Mean (␮g/kg)

Maximum (␮g/kg)

Adapted from Moore et al. (2008).

resident time on farm by reducing the amount of feed per delivery significantly improved bird performance. Improvements in broiler body weight, pigmentation, and carcass grade were also noted when mouldy caked feed was removed from feed delivery trucks, storage silos, conveyors, and feeding troughs by scrubbing and disinfecting (Hamilton, 1975). A recent Australian survey (Moore et al., 2008) investigated the on farm occurrence of aflatoxin, deoxynivalenol and zearalenone in cereal grains, forage and straw (Table 6). The three mycotoxins were found in all commodities with zearalenone having the highest occurrence. Interestingly, grains had the lowest frequency of contamination but are often the only source of mycotoxins considered when examining a field toxicosis. These results highlight the potential risk of contamination of feedstuffs and forages other than grain used in animal production. Moreover, the contamination of straw, which may be used as a roughage source in horse and ruminant diets or as bedding for pigs, poultry and horses, may also be a source of mycotoxin exposure on farm, as can grain dust (Degen, 2011). Farmers are often tempted to incorporate mouldy grain into animal diets to reduce feed costs. However, this practice does carry a risk not only from mycotoxin contamination but in some circumstances, altered nutrient content of the grain. If moulded grains are used in animal diets possible changes in composition, as discussed below, must be accounted for in least cost feed formulations. Moreover, changes in nutrient supply to the animal may alter its response to mycotoxin exposure and complicate diagnosis. 2.4. Mycotoxin analysis Mycotoxins present a major analytical challenge due to the range of chemical compounds that they represent and the vast array of feed matrices in which they are found (Cole, 1986a). Analysis is essential for determining the extent of mycotoxin contamination, for risk analysis, confirming the diagnosis of a mycotoxicosis and for monitoring mycotoxin mitigation strategies. Quantification of these compounds requires sophisticated laboratory equipment including high performance liquid chromatography, gas chromatography, gas chromatography/mass spectrometry or liquid chromatography/mass spectrometry. The interested reader is referred to the following reviews which detail the latest developments in mycotoxin analysis (Gilbert and Anklam, 2002; Maragos, 2004; Logrieco et al., 2005; Krska et al., 2008; Rahmani et al., 2009; Shephard et al., 2011). Despite the sophistication of mycotoxin analysis there are a number of areas that require further study and refinement, including commodity sampling techniques, conjugated toxin determination and field or feed mill screening of feedstuffs. Sampling is the greatest source of error in quantifying mycotoxin contamination (Whitaker, 2003, 2006) because of the difficulty of obtaining feed samples representative of that which may have caused a mycotoxicosis or for regulatory purposes from large grain consignments. These difficulties arise because of the uneven distribution of toxin within a commodity as is demonstrated by aflatoxin distribution in an on farm feed storage silo (Table 7) and the low levels, ranging from ␮g/g to mg/g, at which mycotoxins occur (CAST, 1989, 2003). The relationship of ‘masked’, ‘hidden’, ‘bound’ or conjugated mycotoxins in feedstuffs and the potential for poor animal performance has only recently become apparent. These compounds may be formed as a result of plant metabolism (Gareis et al., 1990; Berthiller et al., 2007) but are not detected with conventional analytical procedures. For example, Table 7 Nonuniformity of aflatoxin occurrence in a feed storage silo.a Sample

Source

Aflatoxin (␮g/kg)

1 2 3 4 5 6

Silo periphery Silo periphery Silo core Silo core Silo core Silo core

120 350 35 <20 <20 <20

a

Adapted from Hamilton (1978).

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Table 8 Mycotoxicoses in non-ruminant farm animals. Mycotoxicosis

Animal species

Mycotoxin

Fungal species

Aflatoxicosis Porcine nephrology Ergotism Fusariotoxicosis, mouldy corn toxicosis Hyperestrogenism or F-2 toxicosis Equine leukoencephalomalacia Porcine pulmonary oedema Tibial dyschodroplasia Haemorrhagic syndrome Stachybotrytoxicosis

Poultry, dogs Pigs, poultry, dogs Poultry, pigs Pigs, poultry Pigs Horses, mules Pigs Poultry Pigs Horses, pigs, poultry

Aflatoxin Ochratoxin A Ergot alkaloid Trichothecenes Zearalenone Fumonisin Fumonisin Fusarochromanone Wortmannin Satratoxins, verrucarin, roridin

Aspergillus flavus, A. parasticus Penicillium verrucosum Claviceps purpurea Fusarium sp F. graminearum F. vericilloides (moniliforme) F. vericilloides (moniliforme Fusarium equiseti Fusarium torulosum Stachybotrys atra

(adapted from Petterrson, 2004)

zearalenone-4-glucoside, a conjugate of zearalenone and deoxynivalenol-3-glucoside a conjugate of deoxynivalenol, can constitute up to 20% of the total content of the precursor mycotoxin in a feedstuff (Berthiller et al., 2005, 2006). It is likely that these conjugates will be hydrolysed following ingestion thus increasing exposure to the precursor toxin. There is also evidence that ochratoxin A and fumonisins are conjugated by plants (Berthiller et al., 2007) and fumonisins may also be conjugated with sugars and proteins during food processing (Humpf and Voss, 2004). Berthiller et al. (2009) have reviewed the formation and determination of conjugated mycotoxins. The development of immunological methods for mycotoxin detection (Pestka, 1994), especially enzyme-linked immunosorbent assays (ELISA), although only semi-quantitative, was a major step forward in the development of rapid, repeatable and sensitive assays. These assays are suitable for field use and the screening of feed commodities in feed mills. Commercial ELISA kits are available for aflatoxins, zearalenone, deoxynivalenol, ochratoxins and fumonisins. There are a number of other approaches, most still experimental, that show promise for rapid mycotoxin analysis without the need of sophisticated equipment (Maragos and Busman, 2010). 3. Mycotoxins and diseases of livestock and poultry The 300–400 secondary fungal metabolites that have been designated as mycotoxins have very different chemical configurations (Cole et al., 2003; Brase et al., 2009). It is not surprising therefore, that mycotoxins are the cause of a number of different animal diseases and those resulting from ingestion of grain-based diets are outlined in Table 8. Mycotoxicoses of grazing animals, including facial eczema (Di Menna et al., 2009), fescue toxicosis (Cross, 2011), lupinosis (van Rensburg et al., 1975), paspalum staggers (Cawdell-Smith et al., 2010), ryegrass staggers (Hunt et al., 1983) and slaframine toxicosis or salivary syndrome (Croom et al., 1995) occur sporadically in horses but mainly in cattle and sheep and have not been included in this discussion. Importantly, diseases arising from ingestion of one or a combination of mycotoxins may affect every system of the body resulting in various clinical signs and lesions; the expression of which, may vary markedly between animal species (see Richard and Thurston, 1986; Haschek et al., 2002). The degree of toxicity will depend on the toxin(s) present, dosage, duration of exposure, and a variety of other factors (Fig. 2). Species, age, hormonal status, nutrition and concurrent disease are considered the most important (Bryden, 2007; Wild, 2007). The gut microflora may also modify mycotoxin toxicity (Swanson et al., 1988; Annison and Bryden, 1998; Eriksen et al., 2002). Much of the interest in the toxicology of mycotoxins arises from the capacity of some to modify the action of DNA (Riley, 1998). As a result of this interaction, mycotoxins may be carcinogenic (e.g. fumonisins), carcinogenic and teratogenic (e.g. ochratoxin A), or carcinogenic, mutagenic and teratogenic (e.g., aflatoxin B1). The teratogenicity of mycotoxins has been demonstrated for some 40 compounds which have been shown to be teratogenic and/or embryotoxic (Cawdell-Smith et al., 2007). These molecular effects of mycotoxins are of particular concern in human populations that have limited food choice and are subjected to low level mycotoxin consumption over many years (Bryden, 2007; Wild and Gong, 2010). In contrast, animal exposure to mycotoxins may result in acute, overt disease or as is usually the case, chronic, insidious exposure that impairs animal productivity. A comprehensive coverage of the mycotoxicoses of livestock and poultry is the subject of a number texts including, Richard and Thurston (1986), Smith and Henderson (1991), Leeson et al. (1995), Diaz (2005), and Oswald and Taranu (2008). In addition, a number of comprehensive reviews have been published on aspects of mycotoxins in poultry (e.g. Dänicke, 2002; Vieira, 2003; Daghir, 2008; Devegowda and Ravikiran, 2008; Girish and Smith, 2008; Hoerr, 2008; Girgis and Smith, 2010; Rawal et al., 2010) and pigs (e.g. van Heugten, 2001; Osweiler, 2006; Tiemann and Dänicke, 2007; Kanora and Maes, 2009). Historical perspectives on animal diseases related to feeds contaminated with aflatoxin (Richard, 2008), DON (Miller et al., 2001), fumonisins (Marasas, 1996), ochratoxin (Krogh, 1987; Marquardt and Frohlich, 1992), zearalenone (Hagler et al., 2001) and Fusarium toxins (Marasas et al., 1984; Morgavi and Riley, 2007) have been published. The general clinical signs of the major mycotoxins are listed in Table 9. The severity of any of these effects in different animal production systems will depend on the level of mycotoxin present in the feed supply chain, the duration of exposure, the physiological status of the animal and other environmental and disease factors that impact on the uptake, biotransformation, deposition and excretion

W.L. Bryden / Animal Feed Science and Technology 173 (2012) 134–158

GENETIC FACTORS

PHYSIOLOGICAL FACTORS

ENVIRONMENTAL FACTORS

Species

Age

Climatic conditions

Breed & Strain

Hormones

Chemicals

Nutrition

Husbandry & Management

141

Intestinal Microflora Infection & Parasitism

MYCOTOXIN

Absorption

METABOLISM

Distribution Biotransformation Excretion

TOXICITY

Biochemical defect

Functional defect

Microscopic anatomical defect

Microscopic (grossly visible) defect

Death Fig. 2. A simplified representation of some general relationships in a mycotoxicosis (Bryden, 1982).

of these toxins. The prominent features of the five mycotoxins considered to be of most global significance (Miller, 1998) are outlined below. 3.1. Aflatoxins Following the outbreak of Turkey X disease in the United Kingdom in 1960 (Blount, 1961) aflatoxin was isolated (Allcroft et al., 1961; Austwick and Ayerst, 1963). The carcinogenicity of aflatoxin was soon identified (Wogan and Newberne, 1967) and the subsequent interest in this group of compounds increased exponentially resulting in the publication of thousands of research papers. Books, including Globlatt (1969), Eaton and Groopman (1994) and Abbas (2005), devoted to aflatoxin have appeared. Aflatoxin is rapidly absorbed and metabolised primarily in the liver in the microsomal system to its active or detoxified metabolites (Riley, 1998; Haschek et al., 2002). The rate of metabolism and products formed determine differences in species

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Table 9 Toxic effects of selected mycotoxins. Mycotoxin

Clinical signs

Aflatoxins

Liver damage; reduced productivity; inferior egg shell and carcass quality; increased susceptibility to disease.

Cyclopiazonic acid

Liver, kidney and gastrointestinal tract damage; weight loss, weakness, egg shell problems; inappetence, diarrhoea, dehydration, depression, opisthotonos and convulsions.

Zearalenone

Swollen, reddened vulva, vaginal prolapse and sometimes rectal prolapse in pigs; suckling piglets may show enlargement of vulvae; fertility problems.

Deoxynivalenol

Decreased feed intake and weight gain in pigs with DON at >2 mg/kg feed; vomiting and feed refusal at very high concentrations of DON (>20 mg/kg diet).

Other trichothecenes T-2 toxin HT-2 toxin Diacetoxyscirpenol Nivalenol

More toxic than DON; reduced feed intake; emesis, skin and gastrointestinal irritation; neurotoxicity; abnormal offspring; increased sensitivity to disease; haemorrhaging.

Ochratoxin A

Mainly affects proximal tubules of the kidneys in pigs and poultry; kidneys are grossly enlarged and pale; fatty livers in poultry.

Fumonisin B1

Equine leucoencephalomalacia (ELEM); porcine pulmonary oedema (PPE); hepatocarcinogenic in rats; and possibly oesophageal cancer in humans.

Ergot alkaloids

Nervous system disorders; tremors; convulsions; diarrhoea; necrosis of the extremities (gangrene); reduced feed intake; abortion, stillbirth and agalactia (cessation of milk production); blackening of the comb, toes and beak in poultry. In high environmental temperatures necrosis of extremities may not be evident but animals may experience hyperthermia.

susceptibility to aflatoxin (JEFCA, 2001; Steyn et al., 2009). It has been demonstrated in many parts of the world, that aflatoxin B1 is a major aetiological factor in hepatocellular carcinoma in individuals infected with hepatitis B virus (Henry et al., 1999; Wild and Hall, 2000). In this instance, the presumed intermediate metabolite, aflatoxin B1 8,9-epoxide forms an adduct with DNA and consequentially disrupts the transcriptional and translational processes. Aflatoxin adducts in urine and blood are reliable biomarkers of aflatoxin exposure (Wild and Turner, 2002). Although it is accepted that aflatoxins are the causative agents of Turkey X disease, Cole (1986b) has presented a persuasive case for the involvement of cyclopiazonic acid (CPA) in this syndrome after reviewing the original reports. The neurological signs (including opisthotonus) and enteritis observed in Turkey X disease are not generally associated with aflatoxicosis but if CPA was also present in the Brazilian groundnut meal that caused the syndrome, then the clinical signs exhibited by the turkey poults could be totally explained (Cole, 1986b). Bradburn et al. (1994) subsequently found CPA in groundnut meal consumed during the original Turkey X disease outbreak. 3.2. Deoxynivalenol Deoxynivalenol (DON) is the most commonly encountered trichothecene and is a type B trichothecene, an epoxysesquiterpenoid. It was originally named “Rd-toxin” by Japanese researchers (Morooka et al., 1972). At about that time, Vesonder et al. (1973) isolated the same compound which they called vomitoxin. Pigs are the most sensitive species to DON and in those species dietary concentrations of 2–5 mg/kg are associated with feed refusal and concentrations >20 mg/kg will induce emesis or vomiting (Haschek et al., 2002). These responses appear to be due to a neurochemical imbalance in the porcine brain. Deoxynivalenol is rapidly metabolised and de-epoxidation via microbes in the gut may be extensive (Eriksen et al., 2002). There is no evidence for tissue accumulation (JEFCA, 2001; Eriksen et al., 2003) of DON nor its transfer into milk (Keese et al., 2008). In animal studies (pigs and poultry) it has been demonstrated that chronic dietary exposure to DON causes impaired weight gain, anorexia, decreased nutritional efficiency and immune dysregulation (Trenholm et al., 1984; Rotter et al., 1996; Haschek et al., 2002). Trichothecenes, including DON can be immunostimulatory or immunosuppressant depending on dose, frequency and duration of exposure (Bondy and Pestka, 2000) and is discussed in more detail below. Implications of continued low level DON ingestion by human populations has been reviewed (Pestka and Smolinski, 2005) and Beasley (1989) has edited a two volume series on the trichothecenes. 3.3. Fumonisins The fumonisins were first isolated by Bezuidenhout et al. (1988) in South Africa and shortly there after as “macrofusine” by Laurent et al. (1989) in New Caledonia. These compounds were isolated from cultures of Fusarium moniliforme which has been reclassified as F. verticilliodes. A number of Fusarium species produce fumonisins, a group of some 12 compounds of which fumonisin B1 is the most studied and most toxic. The toxicity of fumonisins largely reflects its ability to disrupt sphingolipid metabolism by inhibiting the enzyme ceramide synthase; an enzyme responsible for the acylation of sphinganine and sphingosine (Voss et al., 2007; Steyn et al., 2009). The accumulation in tissues of sphinganine initiates a cascade of events

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that may cause toxicity, especially of the liver and kidneys, and carcinogenicity. The ratio of sphinganine/sphingosine in serum, plasma or urine has been used as a biomarker of exposure to fumonisins (Voss et al., 2007). It is now established that the fumonisins cause equine leukoencephalomalacia and porcine pulmonary oedema (Haschek et al., 2002), are carcinogenic in rats (Howard et al., 2001) and may be a major aetiological factor in the incidence of human oesophageal cancer in southern Africa and China (Marasas et al., 2001). Recent epidemiological evidence demonstrate a higher incidence of neural tube defects (NTD) in babies from Texas, China, Guatemala and southern Africa, where the populations rely on foods prepared from maize (Marasas et al., 2004). International surveys of maize for fumonisin contamination has found that there are very few instances where maize can be shown to be totally free of this mycotoxin (Shephard et al., 1996) and this reflects the endophytic relationship of the fungus with maize (Bacon and Hinton, 1996). An association between NTD and fumonisins is likely (Voss et al., 2006) as these mycotoxins induce folate deficiency which is a known cause of neural tube defects in humans (Stevens and Tang, 1997). Recent studies in mice, both in vivo and in vitro have demonstrated that fumonisins may cause neural tube defects (Gelineau-van Waes et al., 2005).

3.4. Ochratoxin van der Mere et al. (1965) isolated ochratoxins from species of Aspergillus and Penicillium. The target organ for ochratoxins is the kidneys and initial interest in this group of toxins was as a cause of porcine nephropathy (Krogh, 1987; Marquardt and Frohlich, 1992). Ochratoxin A has subsequently, been associated with human disorders most noticeably Balkan Endemic Nephropathy in the former Yugoslavia, Chronic Interstitial Nephropathy in northern Africa and kidney tumours (Bayman and Baker, 2006; Pfohl-Leszkowicz and Manderville, 2007). Historically, consumption of pork has been a significant source of human exposure to ochratoxin A in these regions (Jørgensen and Petersen, 2002). Ochratoxin A is genotoxic following oxidative metabolism but its mechanism of inducing disease remains to be fully elucidated (Aish et al., 2004; Pfohl-Leszkowicz and Manderville, 2007; Steyn et al., 2009). However, formation of DNA adducts and oxidative DNA damage appears to be important for the development of carcinogenesis (Pfohl-Leszkowicz and Manderville, 2007). There is ongoing interest in ochratoxin because of its widespread occurrence and involvement in human disease. This research has been given renewed impetus with the recognition that ochratoxin is the major mycotoxin contaminant of wine resulting from infection of the grape berry with black Aspergilli (Varga and Kozakiewicz, 2006; Visconti et al., 2008).

3.5. Zearalenone McErlean (1952) was the first to suggest that Fusarium graminearium (sexual state Gibberella zeae) was the likely source hyperoestrogenism in pigs. Urry et al. (1966) chemically identified the causative compound. The trivial name given to the compound is derived from the following combination; zea-r-a-l-en-one which arise from G. zeae; resorptive acid lactone; ene indicating the presence of the C-1 to C-2 double bond; and one indicating the presence of the C-6 ketone (Hagler et al., 2001). Zearalenone is a non-steroidal oestrogen and its major metabolites ␣-zearalenol and ␤-zearalenol elicit significant oestrogenic activity in animals, corresponding to their binding affinities for hepatic, uterine, mammary and hypothalamic oestrogen receptors (Fink-Gremmels and Malekinejad, 2007). Pigs are very sensitive to zearalenone whereas poultry are very tolerant. Zeranol, a derivative of zearalenone, is used, in some countries, as a growth promotant for sheep and cattle (Baldwin et al., 1983) but not in non-ruminant species. Interestingly, New Zealand research investigating impaired reproductive performance of grazing sheep demonstrated that the sheep were ingesting zearalenone produced on grass (Towers and Sprosen, 1992) and this may have implications for other grazing species, including the horse.

4. Mycotoxins and animal productivity In the preceding section the overt toxicological features of the major mycotoxins have been outlined. However, the major problem associated with mycotoxin contamination of the animal feed supply chain is not acute disease episodes but reduced animal productivity. Low level toxin ingestion may cause an array of metabolic disturbances (Table 10) which may or may not be accompanied by pathological change (Haschek et al., 2002). However, the outcome is invariably poor animal performance which is often difficult to recognise and quantify as the effects in animals and birds are likely to be many and varied. In many instances the effects will be unpredictable as toxicity will depend on many factors (see Fig. 2). It is beyond the scope of this review to describe the manner in which these factors alter tolerance to mycotoxin ingestion. Nevertheless, when considering the discussion below it should be remembered that the animals studied may vary considerably in their response to toxin exposure. For example, broiler strains (Smith and Hamilton, 1970; Bryden et al., 1980) and sex (Bryden et al., 1980) differ in their susceptibility to aflatoxin and selection for resistance to aflatoxin has been demonstrated in Japanese quail (Marks and Wyatt, 1979) and broiler chickens (Wyatt et al., 1987). Moreover, in experiments where fungal culture material was fed and not a pure toxin, responses observed may reflect toxin interactions. This section provides an overview of the important consequences for animal productivity of low level toxin ingestion.

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Table 10 Probable primary biochemical lesions and the early cellular events in the cascade of cellular events leading to toxic cell injury or cellular deregulation of selected mycotoxins.a Mycotoxin

Initial lesion → cascade of events

Aflatoxin

Metabolic activation → DNA modification → cell deregulation → cell death/transformation (metabolic activation → disruption of macromolecular synthesis → cell deregulation → cell death (apoptotic)) Inhibition of protein synthesis → disruption of cytokine regulation → altered cell proliferation → cell death/apoptosis? Sphinganine N-acyltransferase → disrupted lipid metabolism → cell deregulation → cell death/apoptosis (disrupted delta-6-desaturase activity → disrupted fatty acid and arachidonic acid metabolism → cell death) Disruption of phenylalanine metabolism → reduced PEPCK → reduced glyconeogenesis → cell death (metabolic activation → inhibition of protein/DNA synthesis → apoptosis?) (altered membrane permeability → disrupt calcium homeostasis → cell deregulation → cell death) Cytosolic oestrogen receptor → estrogenic response → disruption of hormonal control → ?

Deoxynivalenol Fumonisins Ochratoxin

Zearalenone a

Adapted from Riley (1998).

4.1. Feed intake and growth depression One of the first indications of a chronic mycotoxicosis is growth depression, which may result from reduced feed intake, impaired nutrient utilisation, changes in feed quality or toxicity per se. In a paired-feeding trial, Bryden (1981) demonstrated that the initial responses to aflatoxin ingestion were largely accounted for by reduced intake. However, as the trial progressed the portion of the difference in growth related to differences in feed intake became less indicating that toxicity was inducing anorexia. Studies by Burditt et al. (1983) have shown feed contaminated with T-2 toxin, ochratoxins A, diacetoxyscirpenol, and unknown factors from Penicillium citrinin and Aspergillus ochraceus caused feed refusal in chickens. In pigs, DON is the mycotoxin most often associated with feed refusal. The basis of mycotoxin induced feed refusal has not been fully elucidated but neurochemical mechanisms are probably involved as are physical factors following the development of oral lesions associated with trichothecene ingestion (Brake et al., 2000). Bakau and Bryden (1998) were able to show that ergot alkaloids also cause feed refusal and to demonstrate that chickens will select an uncontaminated diet if offered a choice between a toxin free diet and a diet containing ergot alkaloids. Citrinin has been shown to stimulate water intake (Burditt et al., 1983). This would have implications for litter condition and could increase the build up of ammonia. Following an extensive review of the literature and the application of simple linear regression techniques to literature data, Dersjant-Li et al. (2003) have been able to estimate depression rates of weight gain in broiler chickens and pigs following consumption of diets contaminated with low levels of aflatoxin, DON and fumonisins. It was estimated that with each mg/kg increase of aflatoxin in the diet, the growth rate would be depressed by 16% for pigs and 5% for broilers. For DON with each mg/kg increase in diet the growth depression was estimated to be 8% for pigs while broilers showed no response to DON concentrations below 16 mg/kg. Fumonisin had the lowest impact on growth performance; with each mg/kg increase, the depression of growth rate was estimated to be at 0.4 and 0% for pigs and broilers, respectively. Dietary concentrations that caused a 5% reduction in growth rate were estimated to be 0.3 and 1.0 mg/kg for aflatoxin in pigs and broilers, respectively; 1.8 and 0.6 mg/kg for DON and 251 mg/kg for fumonisins for pigs and broilers, respectively (Dersjant-Li et al., 2003). 4.2. Nutrient utilisation Many studies have demonstrated that mycotoxin ingestion reduced feed conversion efficiency and may reflect impaired nutrient utilisation. Part of the impairment noted in field cases could arise from alterations in nutrient content of heavily moulded grains. Discussions of mycotoxins often neglect the fact that the fungal metabolism and growth that accompanies the elaboration of toxins is likely to change the nutrient composition of the infected feedstuff (Bryden, 1982). Hamilton and his colleagues have examined the influence of Fusarium infection and mycotoxin elaboration on the nutrient value of cereal grains. They have shown that DON levels of 0.7–7.6 mg/kg and zearalenone up to 0.45 mg/kg increased the crude protein, the true metabolisable energy content and the availability to amino acids of wheat (Trenholm et al., 1984). Similar results were observed by this group (Hamilton et al., 1988) in maize when it was contaminated with the same two toxins (Hamilton et al., 1988). Amba et al. (1996) examined 28 samples of maize that contained fumonisins from below the detection level to 14.4 mg/kg and did not find any adverse affect on crude protein, crude fat or apparent metabolisable energy (AME) content. Plant genotypes may be important as Kao and Robinson (1972) were able to show significant changes in levels of amino acids and B-group vitamins when whole wheat grains were moulded with a toxigenic strain of Aspergillus flavus. The degree of change varied with different wheat varieties. In many laboratory studies toxins have been added to non-toxic diets to avoid these confounding effects. Aflatoxin ingestion was without effect on dietary AME content but significantly reduced the energetic efficiency of bodyweight gain, the utilisation of AME for tissue energy gain and increased heat production of broilers (Bryden, 1981). Nitrogen balance was not affected in this study. In other studies with broilers, Verma et al. (2002) observed a significant reduction in net protein utilisation and AME and quantitatively smaller effects when laying hens (Verma et al., 2007) were fed the level of aflatoxin. In a series of calorimetric studies with growing chickens, Rajion and Farrell (1976) concluded that the major effect of aflatoxin was to reduce feed intake with little effect on protein and fat synthesis nor energy utilisation but the rate at which these occur. However these conclusions should be treated cautiously as the mortality rate of the birds receiving aflatoxin was 60%.

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Part of the explanation of decreased nutrient utilisation during mycotoxin ingestion results from a toxin induced malabsorption. This could include, reduced digestion and absorption and increased endogenous loss or contributions from all three. Osborne et al. (1982) demonstrated a marked decrease in digestive enzymes (pancreatic lipase, trypsin, amylase and ribonuclease), steatorrhea, hypocarotenoidaemia, and decreased concentrations of bile salts during aflatoxicosis. The changes were not so marked with T-2 toxicosis and there was a general lack of response by these digestive parameters during ochratoxicosis (Osborne et al., 1982). Recently, in a study with laying hens, Applegate et al. (2009) noted changes in gut morphology and reduced dietary AME values and surmised that aflatoxin has both direct and indirect effects on gut functionality. It has also been shown that DON reduces epithelial cell barrier integrity resulting from perturbations of protein synthesis in vitro in studies porcine intestines (van de Walle et al., 2010). Taken together, these results suggest that disturbances to gut function, including mucosal immunity, could play an important role in subclinical mycotoxicoses. Protein requirements were increased during aflatoxicosis (Smith et al., 1971) and it has been shown that dietary fortification with methionine can alleviate many adverse effects of the toxin in broilers (Veltmann et al., 1981). In a similar study, dietary linoleic acid supplementation was shown to have a growth sparing effect (Lanza et al., 1981a). Earlier studies had shown that diets high in lipid have a mortality-sparing effect against aflatoxicosis (Smith et al., 1971; Hamilton et al., 1972) and, if high in unsaturated fatty acids a growth-sparing effect (Smith et al., 1971). Aflatoxin is known to alter lipid absorption (Osborne and Hamilton, 1981), synthesis (Bryden et al., 1979) and transport to extra-hepatic tissues (Tung et al., 1972). Liver fatty acid composition is significantly changed during aflatoxicosis but the extent of these changes is reduced by the inclusion of dietary biotin (Bryden et al., 1979). Many of the early studies on the interaction between vitamin status and aflatoxicosis gave contradictory results because changes in dietary concentrations of more than one vitamin were examined simultaneously. This shotgun approach made many studies difficult to interpret. Subsequent examination of the interaction of aflatoxin with single-vitamin dietary modifications is more definite. Hamilton et al. (1974) have shown the response of chickens to a single vitamin deficiency is dependent on the vitamin in question. Diets deficient in riboflavin and vitamin D made chickens more sensitive to aflatoxin. However, deficiencies of vitamins E and K had no influence, while a thiamine deficiency had a protective effect against the growth inhibitory effect of aflatoxin. Likewise, Bryden et al. (1979) found that vitamin A deficiency had a protective effect against aflatoxicosis in broiler chickens. It has also been shown that avitaminotic A rats (Reddy et al., 1973) respond differently than adequately fed animals to aflatoxin suggesting that in both rats and chickens vitamin A-deficiency may alter aflatoxin metabolism. Bryden et al. (1979) also noted that if the normal dietary vitamin A concentration was increased tenfold a synergistic effect on mortality and hydropericardium developed and was observed. Surai (2002) has reviewed the effects of mycotoxins on lipid peroxidation and fat soluble vitamins. He was able to show that ochratoxin, T-2 toxin and aflatoxin cause malabsorption which results in impaired absorption and deceased circulating concentrations of vitamins E and C and carotenoid levels in tissues. The literature suggests that mycotoxins promote free radical formation in the intestines which in turn results in antioxidant depletion, oxidative stress, apoptosis which all contribute to the development of malabsorption. Following absorption of mycotoxins they generate free radicals and cause liver peroxidation and damage to other molecules including lipids, proteins and DNA. During avian aflatoxicosis, Lanza et al. (1981b) found that iron absorption is reduced as much 54% and Garlich et al. (1973) found a 20% reduction in circulating levels of calcium. Obviously, impairments in calcium and also in vitamin D3 metabolism would alter skeletal development and both aflatoxin and ochratoxin decrease bone breaking strength (Huff et al., 1980; Devegowda and Ravikiran, 2009). These observations would also have implications for egg shell quality as discussed subsequently. Metabolism in the gut of mycotoxins by the gut microflora may alter toxicity and nutrient utilisation. Swanson et al. (1988) studied, in vitro, the ability of the intestinal micro-organisms to metabolise trichothecenes using species from pig, cow, rat, dog, horse and chicken. The deacylation of trichothecene with acetol side groups occurred in foetal incubates from all species and the deacylation was complete in rats and pigs. Only microbes from rat, pig and cow faeces were able to de-epoxidate T-2 toxin, DAS and DON while no de-epoxidation occurred in faeces from dog, horse and chicken. Eriksen et al. (2002) were able to demonstrate that the gastrointestinal microflora of pigs can metabolise 3-acetyl-deoxynivalenol and nivalenol to their corresponding de-epoxy metabolites and the results show that the de-epoxidation of these mycotoxins is common in commercial piggeries. Other studies have shown transformation of aflatoxin, T-2 toxin, HT-2 toxin, and DON in the rumen (Annison and Bryden, 1998). Degradation of DON in the rumen explains the much lower toxicity of this mycotoxin in ruminants than in non-ruminant species. Likewise, ochratoxin A is much more toxic to non-ruminants as it is rapidly metabolised in the rumen to ochratoxin ␣ and phenylalanine (Müller et al., 2001). 4.3. Reproduction The perturbations of metabolism that occur following mycotoxin ingestion may effect reproductive efficiency of both males and females (Diekman and Green, 1992) and in the pregnant animal, mycotoxins may disturb embryonic and foetal development (Cawdell-Smith et al., 2007). Possible affects on reproduction in poultry are discussed in the next section. Any discussion of mycotoxins and reproduction invariably concentrates on zearalenone. It is an oestrogenic mycotoxin (Hagler et al., 2001) because it mimics the action of oestradiol-17B. The pig is the most sensitive species to zearalenone but the effects of the toxin are modulated by physiological state (Diekman and Green, 1992; Tiemann and Dänicke, 2007; Kanora and Maes, 2009). Prepubertal gilts are the most sensitive to zearalenone exposure and it may interfere with the

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attainment of puberty (Diekman and Green, 1992). In pregnant gilts and sows, zearalenone may increase abortion, stillbirths and neonatal mortality (Kanora and Maes, 2009) through effects on the uterine environment. Following lactation sows exposed to zearalenone may have a prolonged weaning to oestrus interval and in some case may exhibit constant oestrus (Diekman and Green, 1992). Obviously, the severity of these clinical signs are dose dependent as are the effects of the toxin on granulosa cells, steridogenesis and gene expression (Tiemann and Dänicke, 2007; Kanora and Maes, 2009). Other toxins including aflatoxin (Kanora and Maes, 2009) and DON (Tiemann and Dänicke, 2007) largely influence reproduction efficiency indirectly through reduced feed intake and impairment of metabolic function, especially of the liver. Importantly there is evidence of aflatoxin transfer in utero to the developing foetus in both pigs (Pier et al., 1985) and humans (Groopman et al., 2008). Ergot alkaloids may decrease litter size and induce agalactia in sows (Kanora and Maes, 2009) by inhibiting prolactin release (Bryden, 1994). Reproduction can also be seriously compromised in mares grazing tall fescue contaminated with the ergot alkaloid, ergovaline (Cross, 2011). 4.4. Egg production and hatchability In a field outbreak of aflatoxicosis (Hamilton, 1971), egg production dropped to 5%, in an outbreak of T-2 toxicosis rate of production decreased from 72% to 51% (Hamilton, 1982) and the production of hens ingesting ochratoxin dropped from 71% to 61% (Hamilton et al., 1982). Accompanying these production drops was an increase in the incidence of cracked eggs with T-2 toxicosis from 3 to 15% (an additional 18% were cracked after packing) and with ochratoxicosis from 3 to 7%. Aflatoxicosis decreased egg size and there was an increase in the incidence of blood spots from essentially zero to 3% in layers ingesting T-2 toxin. Aflatoxin has been found to be without effect on egg shells (Hamilton and Garlich, 1971), whereas ochratoxin causes thinner and rubbery shells (Hamilton et al., 1982) and T-2 toxin causes thinner and more fragile shells (Wyatt et al., 1975). These observations would also have implications for hatchability. In controlled feeding trials aflatoxin has been shown to cause a delayed decrease in egg production in layers (Garlich et al., 1973) and broiler breeders (Howarth and Wyatt, 1976) and to reduce egg size. A reduction in hatchability has also been noted (Kratzer et al., 1969; Howarth and Wyatt, 1976). The reduction in hatchability may be due, at least in part, to the deposition of aflatoxin into eggs (Sawhney et al., 1973). Qureshi et al. (1998) observed that the chicks of broiler breeder hens that had consumed aflatoxin had immune dysfunction implying increased susceptibility to disease due to humoral and cellular immunity suppression. The effect of aflatoxin on male fertility has given variable results. Briggs et al. (1974) found that neither spermatoza counts or semen volume were altered in broiler breeder males ingesting aflatoxin whereas aflatoxin impaired semen quality in White Leghorn strains (Sharlin et al., 1980). Cyclopiazonic acid (CPA) is a mycotoxin produced by both Aspergillus and Penicillium species. It is often produced by aflatoxigenic strains of Aspergillus flavus and therefore can be found as a co-contaminant in feedstuffs with aflatoxin. Reviews of the occurrence and toxicity of this toxin have been compiled by Bryden (1991) and Bryden et al. (2004). Laying hens ingesting CPA had reduced feed intake and egg production but egg weight was not changed (Cole et al., 1988; Suksupath, 1993). The most notable feature of studies with laying hens is the marked deterioration of egg shell quality that accompanies CPA intoxication and reflects changes in calcium ATPase activity mediated by CPA (Riley, 1998). Suksupath (1993) conducted a 28 day study in which hens were dosed daily with CPA and artificially inseminated weekly. Egg shell thickness was reduced and this was reflected in a reduction in the number of eggs suitable for incubation. The fertility of hens was not diminished by CPA but hatchability dropped by 30%. Of the embryos that failed to hatch all appeared normal and hatched chicks grew normally. On the other hand, CPA reduced semen volume and sperm number and increased the number of abnormal spermatozoa in mature male chickens (Suksupath et al., 1990). 4.5. Immunomodulation The effects of mycotoxins on the immune system are an important consideration when defining the consequences of mycotoxin exposure for animal productivity. It was initially demonstrated at the National Animal Disease Center, Ames, Iowa with aflatoxin, that mycotoxins are immunomodulators, mostly immunosuppressive (see Pier and McLoughlin, 1985; Richard, 2008). Other mycotoxins including aflatoxin, trichothecenes, stachybotryotoxin, ochratoxin A, sterigmatocystin, rubratoxin, fumonisins, zearalenone, patulin, citrinin, wortmannin, fusarochromanone, gliotoxin, fescue and ergot alkaloids have also been shown to increase the susceptibility of animals and birds to infectious disease (CAST, 2003). Substantial evidence exists to show that mycotoxins can be immunosuppressant and exert effects on cellular responses, humoral factors and cytokine mediators of the immune system (Bondy and Pestka, 2000). The interactions between immunity and mycotoxin intake can be very complex (Pestka, 2008). For example, dose, frequency and duration of exposure to DON will determine whether it has an immunostimulatory or immunosuppressant effect (Pestka et al., 2004). Differential gene expression and apoptosis induced by DON are central mechanisms in this immunomodulatory paradox (Pestka, 2008). The effects on immunity and resistance are often difficult to recognise in the field because the signs of disease are associated with the infection rather than the toxin that predisposed the animal to infection (Bondy and Pestka, 2000; Oswald et al., 2005). This is because the immunosuppressant effect of many toxins occurs at lower levels of intake than do the toxin’s effects on production parameters, such as growth rate. Fumonisins and DON commonly co-occur in animal feedstuffs and it has been demonstrated that subclinical co-exposure of pigs to these toxins resulted in greater immune

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Table 11 Poultry and pig diseases known to increase in severity during aflatoxicosis. Species

Disease

Chicken

Candidiasis Coccidiosis Infectious Bronchitis Infectious Bursal Disease Marek’s Disease Salmonellosis

Turkey

Pasteurellosis Salmonellosis

Pig

Erysipelas Salmonellosis

suppression than ingestion of a single toxin (Grenier et al., 2011). Moreover, during infection the body will repartition nutrients away from growth and development to the immune system (Humphrey and Klasing, 2004; Klasing, 2007) and this will further contribute to reduced productivity following mycotoxin exposure. Toxin ingestion can reduce the effectiveness of vaccination programmes (Oswald et al., 2005). Table 11 lists the diseases which are known to increase in severity during aflatoxicosis. The failure of vaccines during aflatoxicosis relates to the immunotoxicity of the toxin which impairs the immune function by decreasing cell-mediated immunity and inducing an inflammatory response (Meissonnier et al., 2008). 4.6. Carcass quality and processing Following aflatoxicosis, broilers have a decreased dressed weight; the carcass contains less fat and protein (Bryden, 1981) and there is a decrease in the yield of breast meat but an increase in the yield of parts or cuts with a smaller meat-to-bone ratio (Doerr et al., 1983). Aflatoxin does effect the outward appearance of the carcass as Doerr et al. (1983) did not observe any change in the incidence of crooked keel, feather follicle infection, breast blisters or other conformation defects. Knowledge of the effect of other mycotoxins on carcass composition and conformation is limited. Chickens ingesting some mycotoxins are sparsely covered with short feathers which protrude at odd angles (Pankhurst et al., 1992). Poor feather cover could result in carcass downgrading rising from blemishes and scratches on exposed skin. It has also been demonstrated that skin pigmentation is reduced during aflatoxicosis (Tung and Hamilton, 1973) and ochratoxicosis (Huff and Hamilton, 1975) due to decreased absorption of dietary carotenoids. This results in downgrading in those countries where the consumer considers carcass pigmentation highly desirable. Carcass downgrading can also result from increased bruising following ingestion of mycotoxins. Aflatoxin causes increased tissue fragility (Tung et al., 1971) and impairment of blood clotting (Doerr et al., 1976). Blood vessels are more easily ruptured and bleed longer and as a consequence the toxin predisposes the bird to bruising from normal handling procedures during catching and slaughter. Associated with the general loss in tissue strength and integrity is a decreased supermarket shelf-like of broiler chickens (Tung et al., 1971). Ochratoxin, rubratoxin and T-2 toxin also impair coagulation function and predispose the bird to bruising (Doerr et al., 1974; Wyatt and Hamilton, 1972). Aflatoxin and ochratoxin act synergistically with regard to bruising (Doerr et al., 1983). Moreover, ochratoxin increases the incidence of carcass condemnations by decreasing the tensile strength of the large intestine, which in turn, is more easily ruptured during processing. 4.7. Tissue residues It is important to know the fate of mycotoxins after ingestion, as contamination of animal products with mycotoxins or their metabolic products has significant public health implications. In this regard, transfer of aflatoxin into milk and ochratoxin A into meat have been the issues of most concern. Available evidence suggests that tissue accumulation of aflatoxin or its metabolites is very low and that residues are excreted in a few days (Stoloff and Rodricks, 1977). Animals are effective toxin eliminators with milk, the animal product most likely to contain aflatoxin residues. The hydroxylated metabolite of aflatoxins B1 , aflatoxins M1 is excreted into milk from 1 to 6% of dietary intake (van Egmond, 1989; Veldman et al., 1992; Fink-Gremmels, 2008). Ochratoxin A has been detected in blood, kidneys, liver and muscle tissue from slaughtered pigs in several European countries (Leistner, 1984; van Egmond and Speijers, 1994). Danish authorities considered pig meat a significant source of exposure for the human population and introduced screening of all pig carcasses in 1978 (Jørgensen and Petersen, 2002). If kidneys showed macroscopic changes of porcine nephropathy, the kidneys were analysed. Ochratoxin A values of 25 ␮g/kg kidney results in the carcass being condemned. This approach has been successful in keeping the toxin at very low levels in pork from Denmark (Jørgensen and Petersen, 2002; Jørgensen, 2005). There are significant differences among pig and poultry tissue deposition studies and this is presumably due to differences in absorption and metabolism of the toxin. It has been shown that the half-life of ochratoxin A in pigs and chickens is 180–140 h and approximately 4 h, respectively (Petterrson, 2004).

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Residues of other mycotoxins including zearalenone, trichothecenes and fumonisins are not considered to be of public health importance as only very low levels of the toxins have been found in the tissues of animals that had been fed very high levels of the toxins in experimental situations (Pestka, 1995; Petterrson, 2004). However, approximately 50% of a dose of CPA administered orally is distributed to skeletal muscle of rats and chickens (Norred et al., 1985, 1988). Other studies have demonstrated that residues of CPA are transferred into milk and eggs (Dorner et al., 1994). Pestka (1995) conducted an extensive review on the possibility of residues occurring in animal products and concluded that trace levels of mycotoxins and their metabolites may carry over into edible tissues of meat producing animals but the evidence suggests that the levels transmitted do not pose a public health risk. However, caution should be exercised when extrapolating or predicting tissue residues as there is presently insufficient data on which to anticipate the outcome of any field toxicosis. For example, a report by Shreeve et al. (1979) suggests that contamination of dairy rations with other mycotoxins, in particular ochratoxin, may decrease the excretion of aflatoxin B1 by dairy cattle. 5. Mitigation of mycotoxin contamination All stockfeeds serve as a suitable substrate for mould growth and mycotoxin production. Once a mycotoxin has been formed in a feed it is difficult to reduce its concentration because of the stability of these compounds (Cole, 1986a). It is therefore important to have strategies that allow the use of contaminated feedstuffs. The obvious approach is dilution with uncontaminated feed. Dilution of mycotoxin-contaminated grain with uncontaminated grain is one of the simplest and most widely utilised methods for improving feed intake and weight gains of animals. However the success of this approach depends on the degree of contamination, the dilution achieved and the availability of a source of uncontaminated grain. In some countries this practice is not permitted. 5.1. Mitigation strategies To reduce the occurrence and the impact of mycotoxins requires an integrated understanding of crop biology, agronomy, fungal ecology, harvesting methods, storage conditions, feed processing and detoxification strategies. It is beyond the scope of this review to describe all of these aspects and the interested reader is directed to Bryden (2009) who has comprehensively reviewed this topic. Overall, there are a number of approaches that can be taken to minimise mycotoxin contamination in the feed chain and these involve prevention of fungal growth and therefore mycotoxin formation, strategies to reduce or eliminate mycotoxins from contaminated feedstuffs or diverting contaminated products to low risk uses including animal feeds. The following general approaches, which apply to the mitigate of mycotoxin contamination of the human food chain (Bryden, 2009) also apply to the animal feed chain; • • • • • • • •

Genetic modification of fungi and crops Agronomic and biological control measures Climate modelling to predict mycotoxin risk Storage management Food processing Detoxification Integrated mycotoxin management Human intervention

Mycotoxin contamination can occur at any stage in the feed production chain and integrated mycotoxin management is an approach that attempts to reduce contamination throughout the chain by applying Hazard Analysis Critical Control Points (HACCP). The successful application of this approach should reduce mycotoxin contamination in all sectors of the chain and have the added advantage of increasing production efficiency (Lopez-Garcia, 2001; Aldred and Magan, 2004). A number of HACCP programmes (Aldred and Magan, 2004; Lopez-Garcia et al., 2008) have been developed for aflatoxin in maize, animal feeds, copra and coconut, groundnuts and pistachio nuts and also for ochratoxin A in coffee. The development of a HACCP program should evolve in conjunction with other complimentary approaches to agricultural production, namely good agricultural practice, good manufacturing practice, good hygiene practice and good storage practice. Therefore, preventive measures begin with good agronomic practices including cultivating to improve plant vigour, the judicious use of insecticides and fungicides to reduce insect and fungal infestation, irrigation to avoid drought stress and harvesting at maturity and, more recently, plant breeding programmes to improve genetic resistance to fungal attack (Bryden, 2009). Attempts to mitigate the effects of mycotoxins in animals have largely concentrated on techniques that reduce exposure to the toxins, especially feed application of binding or trapping agents. This approach is also being explored in human medicine (Phillips et al., 2008) but because complete elimination of mycotoxins from the food chain is extremely difficult, if not impossible, interventions that modify the metabolism and deposition of these toxins have been explored for use in humans (see Kensler et al., 1999, 2004; Groopman et al., 2008). It is unlikely that this approach would be cost effective in animal production. However, feed antioxidants which are used in the feed industry may have a role due to their current use and their ability to induce and/or inhibit key metabolic enzymes. The synthetic antioxidant, butylated hydroxytoluene has

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been shown to be protective against the effects of aflatoxin in turkeys which are one of the most clinically sensitive species to this toxin (Guarisco et al., 2008; Rawal et al., 2010). A very different approach is immunisation which has been attempted for other classes of toxins but there are many problems and progress has been slow and usually disappointing (Cheeke, 1998). A major difficulty with mycotoxins is that they are non-antigenic but this problem has been largely overcome with the development of ELISA procedures (Pestka, 1994). In an innovative study with a mucosal vaccine for aflatoxin B1, the vaccine was able to elicit IgG and intestinal secretory IgA against the toxin in chickens (Wilkinson et al., 2003). As the technology for mycotoxin ELISAs is refined this may provide the basis to further explore mycotoxin vaccines. The effectiveness of vaccines against high mycotoxin doses and multiple toxins would need to be assessed if mycotoxin vaccines become a reality. However, preventive measures to minimise exposure to mycotoxins will be the most cost effective approach for the foreseeable future. As is not possible in this paper to discuss all of the approaches that have been suggested or applied to reduce mycotoxin contamination, the discussion will concentrate on strategies that widely used to reduce the toxicity of contaminated feedstuffs, especially feed storage and processing and the application of feed additives. 5.2. Feed storage and processing Prevention of mycotoxin formation in stored feeds is a major goal in controlling mycotoxicoses in livestock and poultry (Smith and Henderson, 1991). Good feed management practices on farm have been discussed above and apart from methods that modify the fungal environment many compounds are available that will inhibit mould growth in feedstuffs. Organic acids, especially propionic acid, form the basis of many commercial antifungal agents used in the stockfeed industry and give excellent protection (Hamilton, 1985). Approaches to detoxification of mycotoxin contaminated grain and feed have included physical, chemical and biological treatments (Cole, 1989; Trenholm et al., 1989; CAST, 2003; Kabak et al., 2006; Jouany, 2007; Kabak, 2009). In cases of light to moderate mycotoxin contamination, physical methods for cleaning the kernel surface, and hence removing the more heavily contaminated particulate matter, have proven effective in reducing mycotoxin concentrations. A range of chemical treatments have been applied to contaminated products and have been found to vary in their effectiveness at reducing mycotoxin concentrations in contaminated grain or feed (Galvano et al., 2001). Ammoniation has been demonstrated to reduce aflatoxin levels but it is not accepted in the United States as the Food and Drug Administration does not accept the process for the inactivation of aflatoxins (Park and Price, 2001). Ammoniation has also been shown to reduce fumonisin concentrations in maize (Norred et al., 1991). Moreover, the expense of this process would also deter its adoption. All processes that seek to decontaminate infected grain, especially where rigorous chemical or heat treatments are involved, must be cost effective and must not reduce the nutritional content of the grain or feed if they are to be accepted by industry. Few studies have followed the effect of animal feed milling/pelleting/processing on mycotoxin levels in finished feeds. In contrast, any studies have been reported that have followed the levels of mycotoxins in food commodities as they have been processed (see Jackson and Bullerman, 1999; Humpf and Voss, 2004; Murphy et al., 2006). Mycotoxins may appear to be destroyed but in many instances the mycotoxin is not destroyed but accumulates in one fraction of the commodity during the process. In instances where there is only surface colonisation of the grain, removal of bran fractions will remove most of the toxin (Meister and Springer, 2004). In many situations removing screenings from maize will remove the greatest portion of the grain that is contaminated with fumonisins. However, as this can be a substantial fraction of the total amount of grain, this can be uneconomical in many circumstances. Wet milling of maize results in starch almost free of zearalenone, fumonisins, DON and nivalenol. DON and nivalenol are recovered in steep water whereas fumonisins and zearalenone are found mainly in the gluten fraction. In dry milled food products the distribution of mycotoxins among the fractions depends on the fungal penetration of the endosperm (Meister and Springer, 2004; Castells et al., 2005). 5.3. Feed additives The use of feed additives to alleviate nutrient deficiencies, increase product pigmentation, improve pellet quality, breakdown anti-nutritive factors and adsorb toxicants and toxins is a well established practice in the animal feed industry. A diverse variety of substances have been investigated as potential mycotoxin-binding agents (Galvano et al., 2001; Huwig et al., 2001; Jouany, 2007; Oguz, 2011), including lucerne, synthetic cation or anion exchange zeolites, bentonite, spent canola oil, bleaching clays and hydrated sodium calcium aluminosilicate (HSCAS). Successful binding agents work by preventing intestinal absorption of the toxin by the animal from the contaminated feed. Many studies have examined the efficacy of HSCAS to reduce the toxicity of a variety of mycotoxins in livestock and poultry. HSCAS is a high affinity adsorbent for aflatoxins, capable of forming a very stable complex with the toxin and hence reducing its bioavailability but is less effective with other mycotoxins (Phillips, 1999; Phillips et al., 2002). The use of HSCAS to reduce human exposure to aflatoxin is being investigated (Phillips et al., 2008). Dawson et al. (2001) and Jouany (2007) have reviewed the use of a yeast cell wall derived glucomanin prepared for Saccharomyces cerevisiae which has been shown in vitro to efficiently adsorb aflatoxin, zearalenone and fumonisins. While adsorbing, binding or trapping agents can be very effective, additional approaches to detoxifying feedstuffs are required because of the chemical diversity of mycotoxins. Considerable effort has concentrated on isolating microorganisms and/or enzymes that will degrade or metabolise a mycotoxin rendering it nontoxic (Schatzmayr et al., 2006). In this

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regard, a feed additive that is a stabilised bacterium can detoxify trichothecenes by the removal of the epoxide group in vivo (Binder et al., 2001; Fuchs et al., 2002) and is a novel approach to mycotoxin decontamination (Molnar et al., 2004). An exciting development (Heinl et al., 2010) is the isolation and subsequent expression of two enzymes from a soil bacterium (Sphingopyxis sp.) that sequentially deesterify and deaminate fumonisin B1 resulting in degradation of the toxin. The aminotransferase responsible for deaminating hydrolysed fumonisin B1 has been sequenced and expressed in Escherichia coli (Heinl et al., 2011). These outcomes should provide the basis for the enzymatic detoxification of feedstuffs contaminated with this mycotoxin. Many approaches have been used to reduce the toxicity of mycotoxin contaminated commodities. However, most methods have been tested on a limited number of specific toxins. Since contaminated grain may contain a broad range of toxins of differing chemical characteristics, including heat stability, solubility and adsorbent affinity, a detoxification procedure that works well for individual toxins may not be effective for the diverse mycotoxin combinations that may occur naturally. Moreover, no single treatment has proved completely successful in degrading or removing toxins and retaining the nutritional and functional qualities of the treated commodity (Park and Price, 2001). 6. Implications for animal production The foregoing discussion highlights the need to be able to define a mycotoxin related problem and remove contamination from the animal feed chain. It is apparent, however, that as fungi are normal inhabitants of agricultural ecosystems, mycotoxins, which are therefore naturally occurring compounds, will continue to contaminate the feed supply. This scenario has implications for mitigating mycotoxin contaminated feed, as discussed above but also for defining and diagnosing mycotoxin reduced animal productivity, economic consequences both local and international, and feed security. 6.1. Diagnosis of mycotoxicoses If a mycotoxin is the cause of an acute disease episode this is usually quickly established (Richard and Thurston, 1986). However, in many situations mycotoxins cause insidious losses including those related to reduced performance and immunocompetence as detailed in the preceding section. In these cases mycotoxins may be overlooked in the quest for the underlying problem. Diagnosis of a mycotoxicosis in these instances largely depends upon the absence of other readily diagnosed diseases and the finding of a mycotoxin in the suspect feed as it is not enough to isolate a toxigenic fungus (Richard and Thurston, 1986). In the future it should be possible to determine the intake of mycotoxins by animals via the measurement of mycotoxin biomarkers. Development of a robust biomarker requires a detailed understanding of the toxicology of the mycotoxin (Wild, 2007; Groopman et al., 2008). This approach has been successfully applied to determine the exposure of human populations to aflatoxin by measuring aflatoxin albumen adducts in serum (Wild and Turner, 2002). In cases of reduced animal productivity or disease, a mycotoxicosis may be suspected when outbreaks exhibit the following characteristics (Feuell, 1966): • • • • •

The cause is not readily identifiable The condition is not transmissible Syndromes may be associated with certain batches of feed Treatment with antibiotics or other drugs has little effect Outbreaks may be seasonal as weather conditions may affect mould growth

To ascertain that a mycotoxin is the underlying cause of a field problem it is necessary to demonstrate biologically effective concentrations of the toxin in the suspect feed. One difficulty in relying upon chemical analysis of feed is that of obtaining a feed sample representative of that which caused the problem (Whitaker, 2006). It may be difficult to obtain a representative feed sample because of the existence of ‘hot spots’ of fungal proliferation and the resulting uneven distribution of toxin within the feed (Hamilton, 1978; CAST, 1989). Moreover, the production problem may become apparent too late for a sample to be obtained as the feed may have been consumed already. A drop in egg production may not occur until a few days after aflatoxin has been eaten (Hamilton, 1971). This situation could arise in large production units where new consignments of feed arrive weekly and animals could be eating a new consignment of feed before the production drop becomes apparent. In making a diagnosis, not only must mycotoxins be considered for their unique effects, but also they must be evaluated for possible interactions with infectious agents and environmental stressors commonly encountered in animal production (see Fig. 2). Most of the studies reported in the literature are descriptions of experiments that were carried out in an experimental situation with a uniform group of animals that were ingesting a pure toxin that had been added to the diet. Moreover, most laboratory studies use high levels of a toxin whereas in the field, toxin levels are normally low. Therefore it is difficult to extrapolate from the laboratory to a field scenario (Hamilton, 1978). Field situations are often more complicated as animals may be confronted with diets that contain low levels of more than one toxin. For example, aflatoxins, fumonisins, DON and zearalenone can occur together in the same grain (CAST, 2003). Moreover, many fungi produce simultaneously several mycotoxins, especially Fusarium species (Table 3). Toxicity resulting from the interaction between mycotoxins is usually additive and not synergistic as often suggested (CAST, 2003).

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Implicit to these interactions are the existence of syndromes of apparently unknown aetiology and epidemiology and the difficulty of establishing “no effect” levels of mycotoxins under field conditions (Hamilton, 1978). It is important that all those involved in animal production are aware of the possible consequences of mycotoxin contaminated feed; in unexplained instances of poor animal or poultry productivity the possible involvement of a mycotoxin should be considered. Moreover, we will not be able to accurately assess the economic impact of mycotoxins until adequate diagnostic criteria have established that allow quantification of the effects on animal mortality, morbidity and productivity. 6.2. Economic impact of mycotoxins The insidious nature of many mycotoxicoses make it difficult to estimate their incidence and economic impact because of the uncertainty of the level and variability of contamination; variable price of affected commodities, and the costs associated with attempts to mitigate contamination (Lubulwa and Davis, 1995; Robens and Cardwell, 2003). If the various aspects of possible loss during a mycotoxicosis are considered, a multitude of possibilities exist. Obviously, they are complex and deal with many aspects of animal production especially during chronic intoxication. Losses due to death are easy to determine but losses due to morbidity are not easily analysed yet they may be of greater economic significance (Charmley et al., 1994). The economic consequences of the insidious effects of mycotoxins on animal productivity have not been modelled except for a recent perceptive analysis by Wu and Munkvold (2008) of dried distillers’ grain and solubles (DDGS), a co-product of ethanol production from maize. Large quantities of this potentially value animal feedstuff has recently become available but it is generally accepted that the concentration of mycotoxins in DDGS is three times that in the original maize. Wu and Munkvold (2008) were able to show that inclusion of DDGS in pig diets could significantly reduce the profitability of pork production. In the model, only the effects of fumonisins on weight gain were simulated. As Wu and Munkvold (2008) indicate, the total loss to mycotoxins in DDGS (mycotoxins not considered include aflatoxin, DON, zearalenone and ochratoxin A) could be significantly higher due to additive or multiplicative effects of multiple mycotoxins on animal health, Many factors would have to be considered in attempting to determine economic loss in animal production: epidemiological surveys including clinical and laboratory procedures; loss of contaminated feed and cleaning of contaminated feeding equipment; incorporation of antifungal agents into feedstuffs; reduction in animal productivity, increased mortality, and predilection of animals and birds, ingesting mycotoxins, to infection (Charmley et al., 1994). There is also a considerable cost to the industry as a whole, in terms of research, monitoring and extension; extra handling and distribution costs; increased processing costs and loss of consumer confidence in the safety of food products (Lamb and Sternitzke, 2001; Vardon et al., 2003). If the various aspects of loss from mycotoxicoses are considered, one is faced with a multitude of possible impacts. To this list might be added the growing forensic aspect of mycotoxicoses. A Canadian court decision in favour of a pig producer against a feed company (Schiefer and O’Ferrall, 1981) highlights the problems associated with this aspect of fungal infected feed. With the establishment of the high toxicity and carcinogenicity of some mycotoxins, international regulations that limit levels in food and feedstuffs for both man and animals have been imposed (FAO, 2004; van Egmond and Jonker, 2004). These limits have implications for international trade in grain crops and in some instances can result in a barrier for the export or import of commodities from different parts of the world. Interestingly, the outbreak of ‘Turkey X’ disease that occurred in the United Kingdom in 1960 was the result of the importation of peanut meal from Brazil, which was subsequently incorporated into turkey diets and resulted in the death of many thousands of poults (Richard, 2008). This is an example of how the international grain trade can result in the movement of mycotoxins between continents. Wu (2004) completed a comprehensive risk and economic analysis of lowering acceptable levels of fumonisins and aflatoxin in world trade. In that study she demonstrated that the United States would experience significant economic losses from tighter controls. The developing countries China and Argentina were more likely to experience greater economic losses than sub-Saharan Africa. The disturbing outcome of this detailed analysis was that tighter controls were, overall, unlikely to decrease health risks and may have the opposite effect (Wu, 2004). Otsuki et al. (2001) estimated health risks would be reduced by 2.3 deaths per million people per year in the European Union if a lower aflatoxin standard was implemented. In other words, very stringent international trade regulations could lead to the situation where exporting countries, especially developing countries, would retain higher risk commodities, which would be available for their own populations, communities which are already exposed to higher levels of mycotoxins than consumers in developed countries (Wu, 2008). 6.3. Feed security Throughout recorded history mycotoxins have impacted on food and feed security (Matossian, 1989; Ramos et al., 2011) and will remain a threat to global food supplies as a product of plant disease (Strange and Scott, 2005). Mycotoxins demonstrate the continuum from agriculture to human health through plant pathology and nutrition (Scholthof, 2003; Wild, 2007). It has been estimated that some 25% of the worlds grain crops are effected annually by fungal invasion and mycotoxin contamination (Mannon and Johnson, 1985) and with global warming, the threat from fungal invasion of crops is likely to increase (Garrett et al., 2006). The possible impacts of climate change on mycotoxin risks have been the subject of excellent reviews by Magan et al. (2011) and Wu et al. (2011). This is a very complex area of biology that involves predicting changes in ambient temperature, relative humidity, carbon dioxide levels, interrelationships between different fungal genera and

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different crops in different geographical locations (Miller, 2008). Climate change will also change the population dynamics of insects that facilitate fungal infection of crops (Wu et al., 2011) and those that are vectors for animal disease (Slenning, 2010). Obviously, the risk of mycotoxin contamination is very dependent on the country or region in which crops are grown. In addition to climate change, any realistic assessment of the future risk of animal exposure to mycotoxins must take into account a number of significant global trends. The world population is increasing rapidly, there is increased competition between humans and animals for food commodities as developing countries increase their appetite for animal products (Cheeke, 2004; Farrell, 2010) and an increasing proportion of edible grain is being diverted to biofuel production (Wu and Munkvold, 2008). All of these trends increase the uncertainty of future feed supply. There will be a greater reliance on a more diverse range of animal feed sources which may also be of a lower quality. Changes of this nature to the feed commodities used in animal production will bring with it corresponding changes in the mycotoxins encountered and the level of contamination. This is exemplified, in many respects, by the increasing use of DDGS in animal diets (Wu and Munkvold, 2008). Due to these trends and the ubiquitous nature of toxigenic fungi there will be increased attempts to detoxify or counteract the mycotoxin contamination of feed commodities. Along with benefits of new or improved approaches to mycotoxin mitigation every effort should be made to identify any risks associated with widespread use of new feedstuffs and new technologies. 7. Conclusions Mycotoxins pose a significant risk to the health and wellbeing of humans and animals and are a significant food safety issue. Despite the research effort that has attempted to delineate the multiple aspects of mycotoxin contamination of the human food and animal feed supply chains, many questions remain unanswered. Although mycotoxicoses have been known for centuries, it is only in the last 50 years that we have achieved an understanding of the production, chemistry and biological effects of these natural feed contaminants (Richard, 2007). In that time, strategies have been developed, including agronomic practices, plant breeding and transgenics, biotechnology, toxin binding and deactivating feed additives, and education of feed suppliers and animal producers to reduce mycotoxin contamination and exposure (Bryden, 2009). Nevertheless, it has proven difficult to control exposure of man and animals to these natural environmental compounds. This is a significant issue for both food and feed security globally and we will have to live with some degree of risk. 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