Worldwide Occurrence of Mycotoxins in Cereals and Cereal-Derived

Dec 15, 2016 - On the basis of the global occurrence data reported during the past 10 years, the incidences and maximum levels in raw cereal grains we...
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Worldwide Occurrence of Mycotoxins in Cereals and Cereal Derived Food Products: Public Health Perspectives of Their Co-Occurrence Hyun Jung Lee, and Dojin Ryu J. Agric. Food Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jafc.6b04847 • Publication Date (Web): 15 Dec 2016 Downloaded from http://pubs.acs.org on December 20, 2016

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Journal of Agricultural and Food Chemistry

Worldwide Occurrence of Mycotoxins in Cereals and Cereal Derived Food Products: Public Health Perspectives of Their Co-Occurrence

Hyun Jung Lee and Dojin Ryu*

School of Food Science, University of Idaho, 875 Perimeter Drive MS 2312, Moscow, Idaho 83844, USA

*Corresponding author: Tel: (208) 885-0166; Email: [email protected]

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Cereal grains and their processed food products are frequently contaminated with mycotoxins.

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Among many, five major mycotoxins of aflatoxins, ochratoxins, fumonisins, deoxynivalenol,

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and zearalenone are of significant public health concern as they can cause adverse effects in

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human. Being airborne or soilborne, cosmopolitan nature of the mycotoxigenic fungi contribute

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to the worldwide occurrence of mycotoxins. Based on the global occurrence data reported

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during the last ten years, the incidences and maximum levels in raw cereal grains were 55% and

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1,642 µg/kg for aflatoxins, 29% and 1,164 µg/kg for ochratoxin A, 61% and 71,121 µg/kg for

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fumonisins, 58% and 41,157 µg/kg, for deoxynivalenol, and 46% and 3,049 µg/kg for

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zearalenone. The concentrations of mycotoxins tend to be lower in processed food products

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while the incidences varied depend on the individual mycotoxins possibly due to the varying

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stability during processing and distribution of mycotoxins. It should be noted that more than one

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mycotoxin may occur in various combinations in a given sample or food, that are produced by

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single or several fungal species. Most studies reported additive or synergistic effects, suggesting

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that these mixtures may pose a significant threat to public health particularly to infants and

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young children. Therefore, information on co-occurrence of mycotoxins and its interactive

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toxicity are summarized in this paper.

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Keywords: Mycotoxins, cereals, co-occurrence, combined toxicity.

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Journal of Agricultural and Food Chemistry

Introduction Mycotoxins are extracellular metabolites of filamentous fungi that can cause acute or

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chronic toxicity in animals and humans. While mycotoxins are a large and diverse group of

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naturally occurring chemicals, those of importance in public health are mainly produced by

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certain strains in the three fungal genera, i.e. Aspergillus, Penicillium, and Fusarium. Cereal

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grains are commonly contaminated with various fungal species and the initial infestation, growth,

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and subsequent mycotoxin production mainly happens during the cultivation and/or during the

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storage of the crops (Fig. 1). The fungal infestation and mycotoxin production is largely

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dependent on environmental factors such as temperature and moisture at any given stage. It

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should be noted that the presence or infestation of mycotoxin-producing fungi in cereal grains is

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not always conducive to contamination with mycotoxins since it requires stresses by several

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factors to produce mycotoxins.1 Nonetheless the presence of toxigenic fungi still poses a

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potential risk of contamination with mycotoxins. Several control points, such as selection and

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development of resistant cultivars with conventional breeding or biotechnology, Good

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Agricultural Practices (GAP), chemical and biological control during the cultivation, and proper

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management during the storage, may reduce the fungal infestation and growth as well as

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mycotoxin production in cereal grains.

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It has been estimated that a large number of mycotoxins exist: approximately 300 to

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20,000 to even 300,000.2-4 However, regardless of the number of “estimated” toxic secondary

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metabolites, mycotoxins of concern in public health may be identified as aflatoxins (AFs),

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ochratoxin A (OTA), fumonisins (FBs), deoxynivalenol (DON), and zearalenone (ZEN). As

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their chemical nature varies (Fig. 2), toxicities of mycotoxins as well as the target organs in

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animals and humans also vary significantly, e.g. carcinogenic, teratogenic, hepatotoxic,

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nephrotoxic, immunosuppressive, etc., as summarized in Table 1.

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A mycotoxin is generally produced by closely related species, e.g. AFs are produced by a

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few species in the genus Aspergillus. However, OTA is produced by Aspergillus spp. or

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Penicillium spp. depend on the commodity and environmental conditions. And in some cases

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single Fusarium spp. can form more than one mycotoxin, e.g. DON, and ZEN. Hence,

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mycotoxins are regulated in many countries worldwide including EU and the U.S. at varying

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levels for cereal grains and their derived products (Table 2). As it is practically impossible to

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eliminate mycotoxins in foods once contaminated, partly due to the stable nature of mycotoxins

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during food processing, strategies to minimize human exposure, such as limiting maximum

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levels in the commodities commonly contaminated, must be considered carefully. More

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importantly, the occurrence of mycotoxins in foods should be monitored closely to assess the

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risks associated with mycotoxins in the evolving consumer demand and agricultural conditions

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including global climate variability. Hence, this review summarizes the occurrence of major

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mycotoxins reported in the last ten years worldwide with emphasis on the co-occurrence of

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multiple mycotoxins in cereal grains and their derived products. It also coincides with the

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development in analytical techniques, i.e. increased availability of liquid chromatography

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coupled with mass spectrometry, which enabled detection of multiple mycotoxins

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simultaneously. In addition, experimental data on the combined toxicity of the major

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mycotoxins are included.

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Aflatoxins (AFs)

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Following the Turkey X disease in England in1960, AFs have been researched widely and known to be most toxic among all mycotoxins and pose the greatest threat in human health.

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Among the known analogs in this group, four of them are more significant in foods: AFB1, AFB2,

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AFG1, and AFG2 in cereal grains and cereal derived food products that are produced mainly by

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Aspergillus flavus and A. parasiticus.5 In addition, AFM1 and AFM2, two major metabolites of

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AFs, are found in milk and dairy products. AFs production occurs primarily in nuts and cereals

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under conditions of high temperature and humidity such as regions in tropical or subtropical

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climates while it may be stimulated by drought stress. Among all analogs of AFs, AFB1 is most

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toxic and occurs most frequently with highest concentrations. AFB1 is a potent

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hepatocarcinogen and has been classified as Group 1, i.e. carcinogenic to humans, by the

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International Agency of Research on Cancer (IARC).6 Not only that, AFs are

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immunosuppressive, mutagenic, and teratogenic compound, and the main target organ for

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toxicity is the liver. As shown in Table 2, the European Commission (EC) set maximum limits

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for AFB1 and total AFs at 2 and 4 µg/kg in cereals, respectively.7-8 The U.S. Food and Drug

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Administration (FDA) has set action levels for AFs; total AFs of 20 µg/kg in foods.9

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Ochratoxin A (OTA)

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Ochratoxin A is the most toxic among its analogs and is produced by a number of species

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in two distinctively different fungal genera of Aspergillus and Penicillium.10-12 Notable OTA

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producers include A. ochraceus, A. carbonarius, and P. verrucosum. It should be noted that

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organisms in two distinctively different fungal genera can produce OTA. For instance,

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temperatures to produce OTA are 12 – 37°C for A.ochraceus and 0 – 31°C for P. verrucosum.

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This means that OTA may be produced in all agricultural regions in the world by either of the

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species. Hence, these fungi and OTA can contaminate exceptionally wide range of agricultural

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commodities and processed foods including all major cereal grains, nuts, dried fruits, wine, beer,

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cocoa, green coffee beans, etc.13-17 OTA has been classified as a possible human carcinogen

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(Group 2B) by IARC, and the main target organ is the kidney.6 In addition, OTA is known to be

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teratogenic, embryotoxic, genotoxic, neurotoxic, and immunosuppressive in various in vitro and

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in vivo models.18-20 However, its impact on human health and toxicity mechanism are largely

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unclear. The EC set maximum limits for OTA; 5 µg/kg in unprocessed cereals, 3 µg/kg in

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processed cereal derived products, 0.5 µg/kg in baby food for infant or young children. Recently,

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Canada proposed similar regulatory guidelines.21 At present, there are no guidance or action

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levels for OTA in foods in the U.S.

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Fumonisins (FBs)

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Fumonisins are produced mainly by Fusarium verticillioides and F. proliferatum.5 As

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many Fusarium spp. are important plant pathogens, this group of mycotoxins, fumonisin B1 (FB1)

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in particular, is often accompanied with recognizable diseases of the plant such as ear rot in

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maize which may also be caused by other Fusarium species including F. graminearum. In

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addition, endophytic nature of the fungal pathogens is a major contributing factor for the

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contamination of fumonisins worldwide particularly in maize.22-24 Among all analogs of

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fumonisins, FB1 is known to be most toxic and occurs most frequently.25 FB1 has been found to

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be a potent cancer promoter, and its major target organs are the kidney and liver,26-28 thus IARC

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classified FB1 as a possible human carcinogen (Group 2B). The EC has recommended guidance

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levels for sum of FB1 and FB2 (Table 2). The FDA has set action level for total fumonisins

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between 2 – 4 mg/kg.

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Deoxynivalenol (DON)

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DON, also known as vomitoxin, is one of the most commonly occurring trichothecenes in

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cereals and cereal derived food products. F. graminearum and F. culmorum are consistent

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producers of DON in cereals, such as wheat, barley, oats, and corn.29 Other notable

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trichothecenes commonly found in cereal grains include T-2 toxin and nivalenol. DON cause

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vomiting, feed refusal, and teratogenicity based on animal study.30-31 While DON is listed as a

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Group 3 (not classifiable as to its carcinogenicity to human),6 gastroenteritis with vomiting have

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been observed in human.32 DON is also known to be immunosuppressive in animal and human

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lymphocytes.33-34 Since its toxicity and widespread occurrence, DON has received particular

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attention in recent years. The EC and the FDA have recommended maximum limits for DON in

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cereals and its derived food products.9, 35

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Zearalenone (ZEN) ZEN is a non-steroidal oestrogenic mycotoxins produced by F. graminearum and F.

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culmorum, that may also produce DON. These soilborne fungi are common in temperate and

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warm climate regions, causing disease in the host plant such as Fusarium head blight in wheat

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and barley and ear rot in maize.36 ZEN is one of the most common mycotoxins contaminating

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wheat, rye, and oats in European countries as well as corn and wheat in the U.S. and Canada.

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ZEN has been observed to competitively bind to oestrogen receptors in various animal models.37-

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38

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but classified Group 3.6 Maximum limits for ZEN in cereals and cereal derived food products

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were established by the EC (Table 2).

ZEN also caused carcinogenicity, hepatotoxicity, genotoxicity, and immunosuppression,39-41

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Occurrence of mycotoxins in cereals and cereal-based products A number of studies on the occurrence of mycotoxins in cereals and cereal derived food

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products have been published. As this review aims at providing an update on mycotoxin

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contamination in cereals and cereal derived food products, only publications dating from 2006 or

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later, i.e. 104 papers, were included. These data clearly show that mycotoxins are ubiquitously

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present in cereals and cereal derived food products throughout the world. Table 3 summarizes

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the incidences and the ranges among the positive samples of major mycotoxins by commodities

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and geographic regions. While these data may not provide enough information to assess the

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exposure and/or risks associated with the mycotoxins, they could be considered as indicators to

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estimate and compare occurrence of major mycotoxins around the world. In this regards, future

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studies need to address the significance of mycotoxin contamination problems with emphasis on

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the implication of such survey data, e.g. incidences and ranges above the guidance levels. This is

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particularly true in considering recent advances in analytical methods that can detect much lower

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concentrations of targeted mycotoxins than those levels pose public health concerns.

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Occurrence of AFs

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The occurrence data from the 31 papers published during the last decade show that AFs

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continue to be a significant concern in the most part of the world particularly in Africa with the

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incidence rate of 50% in raw cereal grains with the highest level of 1,642 µg/kg detected in rice.

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In Asia, where rice is the major staple crop, the highest level of contamination reported was 850

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µg/kg from corn even when the overall incidence was very high at 63%. Although the number

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of samples collected in Asia was much greater than those collected in Africa, the difference

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between the highest level of contamination in the samples from Africa and those from Asia

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indicates that the environmental conditions in Asia are less favorable for the production of

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aflatoxins in grains. In contrast, nearly 1,400 µg/kg of AFs was found in maize from South

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America even with the lowest incidence rate of 15%, while Europe recorded lowest

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contamination level of 33 µg/kg with the incidence rate of 44%. These data suggest that AFs

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occur more sporadically especially in corn while its level of contamination can vary greatly

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depend on the regions and climate conditions. In general, lower rates of incidence and

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contamination levels were found in processed foods in comparison with the raw cereal grains.

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However, in Africa and America where corn is more frequently used, the incidences of AFs in

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their processed products were higher although the concentrations were lower. It suggests that the

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contamination of AFs could be managed during the processing.

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Occurrence of OTA

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For the occurrence of OTA, among about 4,000 samples surveyed in 33 different reports,

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incidences in raw cereals and processed products were 29% and 38%, respectively. The highest

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level of OTA (1,164 µg/kg) was detected in rice samples from Africa.42 It should be noted that

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the incidences, and more importantly the levels of contamination, observed in processed foods

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were similar or higher than those in raw grains in all regions except Africa where the data was

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not available. In Europe in particular, both incidence and the levels were higher than those of

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raw grains indicating contamination of ingredients other than cereal grains. This may be due to

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the lack of attention or proper management practices in the supply chain despite the stringent

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regulations especially in EU and/or greater stability of OTA than other mycotoxins during food

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processing.

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It would be of interest to note that oats and oat-based products are more commonly

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contaminated with OTA than other cereals and cereal based products. According to recent

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surveys conducted in the U.S., OTA ranging 0.1 – 9.3 µg/kg was found in 205 out of 489 (42%)

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retail breakfast cereal samples.43-44 Among all product groups tested, highest incidence rate of

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70% (142/203) was found in oat-based breakfast cereals.43-44 More significantly, 59% (30/51) of

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the oat-based infant cereals were highly contaminated with OTA in the range of 0.6 to 22.1

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µg/kg.45 In considering the EU’s maximum limit of OTA is 0.5 µg/kg for infant foods, such high

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levels of contamination are alarming public health concern.

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Occurrence of FBs The occurrence data were obtained from 26 different reports (total 1,284 samples) and

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were organized by continents (Table 3). Fumonisins are most prevalent in North and South

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Americas with the highest incidence rate of 95% (249/261) and level of contamination ranged 10

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– 34,700 µg/kg in raw cereal grains. The incidence of 62% was reported from both Asia and

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Africa with the highest level of 17,121 µg/kg and 24,225 µg/kg, respectively. Europe showed

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the lowest incidence of FBs (39%, 195/495) with the highest concentration at 5,400 µ/kg. While

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the occurrence of FBs in raw cereals varied significantly by the regions, both incidences (25 –

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39%) and upper contamination levels (1,670 – 3,310 µg/kg) in processed foods were relatively

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similar in all regions except Africa where there no data was available. Regardless of the regions,

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corn showed the highest incidence and contamination, which may be attributed to the endophytic

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nature of the fumonisin producers particularly F. verticillioides. It may also be due to the

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chemical nature of fumonisins, i.e. water soluble and less heat stable than other mycotoxins.

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Occurrence of DON

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DON seems quite common in all regions with 59% of average incidence rate, ranging

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from 50% in Asia to 76% in Africa, but tends to occur at higher concentrations in Europe and

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Asia. While the highest concentration (41,157 µg/kg) was detected in wheat from China,46 DON

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was most commonly found in wheat and wheat based product with higher levels of

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contamination worldwide. As the occurrence or prevalence of fumonisins in maize, association

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of DON with wheats can be attributed to the characteristics of its major producers, i.e.

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distribution of F. graminearum and F. culmorum in all wheat growing regions and the

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environmental factors affecting their growth and toxin production. In processed foods, the levels

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of contamination were significantly less than those in raw cereals suggesting that the toxin may

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be managed and/or reduced during the postharvest handling and processing.47-49

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Since DON is mainly accumulated and located near the bran portion of the grain, DON

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levels in the flour tend to be lower after fractionation during milling process.50 Generally,

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harvested grains are converted into flour and other fractions (germ and bran fractions) during

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milling process, for human consumption or further food processing. Nonetheless, global average

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of incidence in processed foods was 56% indicating that DON, similar to other mycotoxins, may

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not be removed completely once it enters the food chain.

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Occurrence of ZEN

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While ZEN was not as prevalent as DON, incidences reported from African and Europe

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were over 50% followed by Americas with 48% from unprocessed cereals. In Asia where the

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incidence was the lowest at 15%, moderately high level of ZEN (3,049 µg/kg) was detected in

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wheat samples. It is highly plausible to find DON and ZEN simultaneously in wheats as they are

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often produced by the same fungi, i.e. F. graminearum and F. culmorum. Nonetheless, higher

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concentrations of ZEN have been found in maize and rice as the growing conditions, i.e. warmer

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climate, for these crops are more favorable for ZEN production by the same organisms. Similar

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to the case of FBs, both incidences and concentrations of ZEN were reduced significantly after

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processing in all regions. This again reflects the fact that ZEN is not as stable as AFs and OTA

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during food processing.

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Co-occurrence of mycotoxins Foods are often contaminated with multiple mycotoxins because some fungi, particularly Fusarium spp., can produce more than one mycotoxin and/or several toxigenic fungi can

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contaminate a food or commodity simultaneously. The latter may be regarded realistic when

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considering the periods of storage as well as cultivation in the field. Co-contamination or co-

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exposure is also very plausible due to the varied diet on our table consists of different

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commodities, possibly many. Hence, co-occurrence of mycotoxins raises a concern in public

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health due to the current guidelines and risk assessments are largely based on the toxicity studies

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with each individual mycotoxin where interaction among multiple toxins in foods or diet may

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result in varying impact on human health. Consequently, recent surveys on mycotoxins have

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paid greater attention to the co-occurrence in foods, while most of the earlier surveys focused on

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the occurrence of single toxins in foods. Development of analytical techniques particularly LC-

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MS/MS methods enabled simultaneous identification and quantification of multiple mycotoxins

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at low levels.

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According to Biomin’s global mycotoxin occurrence reports,51-52 samples contaminated

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with more than one mycotoxin were 41% in 2011 (n=4,327) and 45% in 2013 (n=4,218).

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Another report from Biomin29 also showed that co-occurrence of mycotoxins is common – 48%

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were contaminated with two or more while 33% were contaminated with single mycotoxin

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among a total of 7,049 samples from in North and South Americas, Europe and Asia collected

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from 2009 to 2011. These occurrence data should be interpreted with caution as foods for

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human consumption were not included but only feed materials. Nonetheless, these data suggests

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the prevalence of co-existing mycotoxins in cereal grains.

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The co-occurrence of mycotoxins represents the common nature, i.e. fungal

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contamination in the environment, as the prevalence of co-occurrence in cereals and cereal

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derived food products worldwide has been documented. Several bio-monitoring studies have

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been performed to investigate the exposure to multiple mycotoxins based on those co-

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contamination reports. Recent human exposure assessment surveys, using LC-MS/MS for the

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measurement of multi-mycotoxins and their metabolites in urine, showed that 18-100% of the

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samples contained urinary biomarkers related to mycotoxins. According to Abia et al. 53 five

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mycotoxins or their metabolites were detected in one urine sample while two or more

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mycotoxins were found in 18% (32/175) of the samples collected in Cameroon. In the two

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surveys conducted in Germany, multiple mycotoxins were found in 38% (19/50) and 50%

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(51/101) of the samples.54-55 In addition, more than one mycotoxin was detected in 25%

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(35/142), 64% (61/95), and 69% (173/252) of the urine samples from Haiti,54 Bangladesh,54 and

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Sweden,56 respectively. It is also notable that Solfrizzo et al. 57 found more than one mycotoxin

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in 100% (52/52) and up to five mycotoxins in 4% (2/52) of the urine samples from southern Italy.

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Toxicity of combined mycotoxins Most of the earlier researches about the occurrence and/or toxicity including their

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mechanisms were focused on single mycotoxins. However, as stated above cereal grains and

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cereal-based products are often contaminated with more than one mycotoxin. Consequently,

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human can be exposed to multiple mycotoxins at the same time. The potential risk of chronic

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exposure to multiple mycotoxins from co-contamination in food may lead to a greater toxicity

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than exposure to single mycotoxin. With an increased emphasis on the co-occurrence of

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mycotoxins for updating safety guidelines, studies on combined toxicity of major mycotoxins

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deserve attention while the numbers are limited.

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Predicting or interpreting combined toxicity data is challenging. It is commonly assumed

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that mycotoxins with the same mechanism of action and/or target organs would have synergistic

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or at least additive effect when combined together.58 However, the combined toxicity of mixed

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mycotoxins cannot always be predicted solely on the toxicity of individual mycotoxin59 since the

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combined toxicity can be influenced by several factors (Figure 3) such as (i) chemistry,

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mechanism of action, and toxicokinetics of mycotoxins in the cell or body; ii) experimental

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design including the dose and type of cells or animal models as well as their endpoints; and iii)

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statistical methods applied.58, 60 In general, experimental design to study combined toxicity is a

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two-step approach Sühnel 61, i.e. dose-response analysis of individual mycotoxin followed by

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combined toxicity study. Researchers have used in vivo models, i.e. various experimental

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animals, to study toxicity mechanisms of individual or combined mycotoxins. By far animal

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models are most helpful to understand the metabolism and mechanism thus effectively estimate

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the toxicity that may occur in humans. Different species of animals, age and sex, dose and

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treatment duration, and the route of exposure of combined mycotoxins should be considered

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depending on the type of toxicity and end points. Until now, most of the combined toxicity

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studies published using in vitro and in vivo models focused on the interactions of AFB1 or OTA

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with other mycotoxins. This review summarized the findings on the combined toxicity of

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mycotoxins based on published papers from 2001 to 2016

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Interactions between AFB1 and OTA AFB1 is genotoxic and a potent hepatocarcinogen while it may also cause tumors in other

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organs including kidneys.62 The toxicity and carcinogenicity of AFB1 are linked to the

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bioactivation as a part of detoxification process in the liver by cytochrome P450 into its epoxide

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metabolite (AFB1-8,9-exo-epoxide) which binds to DNA, RNA, and proteins to form adducts.63-

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64

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in the organ.65-67 OTA is also hepatotoxic while it is known to be nephrotoxic and genotoxic,

The kidneys also take part in the process as the residues of detoxification have been detected

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thus a possible carcinogen to humans68-74 though the exact mechanism of toxicity is not clearly

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understood.

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According to Golli‐Bennour et al. 75, the combination of AFB1 and OTA caused additive

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effect in monkey kidney (Vero) cells as they observed decreased cell viability, increased DNA

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fragmentation and expression of p53 activation, and decreased expression of the antiapoptotic

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factor bcl-2 protein.75 Corcuera et al. 76 also observed additive effects in human hepatoma

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(HepG2) cells when mixture of OTA and AFB1 were treated for 24 hrs showing genotoxicity

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determined by the modified comet assay with restriction enzymes. This study demonstrated that

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DNA damage induced by AFB1 was decreased significantly by co-exposure to OTA suggesting

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AFB1 and OTA complete for the same CYP enzymes which represent the bioactive route for

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AFB1. In a following study with F344 rats, acute toxicity of AFB1 (0.25 mg/kg body weight

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(b.w.)) in the liver was decreased when OTA (0.5 mg/kg b.w.) was administered in combination

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with no observed toxicity in the kidneys.77 On the other hand, Abdel-Wahhab et al. 78 observed

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that combination of AFB1 and OTA caused more pronounced liver and kidney damages and

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increased oxidative stress in the liver of SD rats than either toxin alone. In the biochemical

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analysis, parameters related to liver and kidney functions showed synergistic when the two

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mycotoxins were combined. They conclude that decreased antioxidant capacity by the combined

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treatment of AFB1 and OTA might lead to an increase in oxidative DNA damage.78

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Both AFB1 and OTA have been reported to be teratogenic in animals.79-82 Studies on the

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combined prenatal effects of these mycotoxins are insufficient, but when used in combination,

313

AFB1 and OTA showed antagonistic interaction in rats.83-84 The anencephaly, incomplete

314

closure of skull, wavy and fused ribs, agenesis of the ischium bone, and enlarged renal pelvis,

315

resulted from OTA treatment and ear abnormality and incomplete ossification of skull bones

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caused by AFB1 when given individually, were not seen in these two mycotoxins combination

317

treated groups.83 However, gastroschisis, syndactyly, and increased incidence of cardiac defect

318

were observed in the groups treated with combined mycotoxins.83 In another study,85 mortality

319

in any of the treated groups was not observed when AFB1 and OTA alone or in combination

320

were administered to New Zealand White rabbits during 6 – 18 days of gestation. Moreover,

321

most of the gross, skeletal and visceral anomalies observed in individual AFB1 or OTA treatment

322

were either reduced or absent in combination treated groups.85 They also demonstrated

323

antagonistic interactions of AFB1 and OTA in teratogenicity model using post-implantation of rat

324

embryos in culture, i.e. the embryo weights, somite numbers, and neural tube development were

325

less severely affected than when either AFB1 or OTA was treated alone. Hence, it was suggested

326

that AFB1 may inhibit the biotransformation of OTA in the liver as both AFB1 and OTA are

327

metabolized mainly by the hepatic cytochrome P450.86-87 This potential mechanism was further

328

elucidated as the antagonistic effects of the combined mycotoxins on the protein, DNA, and

329

RNA contents was observed when S9 mix was present, suggesting the biotransformation of

330

AFB1 or OTA in the liver might have played some role.

331

Interactions between AFB1 and Fusarium mycotoxins

332

Most of the combined toxicity studies involving AFB1 have been performed focused on

333

the interactions between AFB1 and Fusarium mycotoxins, especially FB1, since those two

334

mycotoxins are found to naturally co-occur in cereal grains and share a common target organ.

335

As mentioned above, kidney is considered as one of the target organs of AFB1 though it targets

336

mainly the liver.62, 88 Previous reports showed that FB1 can induce apoptosis in kidney and liver

337

in various in vitro and/or in vivo models,89-91 which may be caused by the inhibition of

338

sphinganine (Sa) N-acetyl transferase and disruption of the de novo biosynthesis of sphingosine

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(So).92 Hence, toxicity studies with AFB1 and FB1 on various organisms have performed and

340

reported their interactions ranging from non-interacting to synergistic with different end points.

341

Dilkin et al. 93 reported that there was no interaction between AFB1 and FB1 when these

342

two toxins were orally administered to weaned piglets for 28 days with decreased feed

343

consumption during the last week (week 4) and feed conversion throughout the period. In mice,

344

only AST increased significantly after feeding AFB1 and FB1 for 90 days while the body weight

345

gain did not show significant variations among treated groups.94 However, Tessari et al. 95

346

observed reduced body weight, vacuolar degeneration and cell proliferation of bile ducts in liver

347

and hydropic degeneration in renal tubules in broiler chicks treated in combination of AFB1 and

348

FB1. Later, increased plasma total protein, bile duct proliferation and trabecular disorder in liver

349

was also observed by the same group.96

350

Evidence of synergism between AFB1 and FB1 also exists. Compared to the rats treated

351

singly with AFB1 or FB1, animals treated both toxins in sequence, i.e. AFB1 for two weeks

352

followed by FB1 for three weeks, showed increased liver weight, cirrhotic livers, apoptosis, and

353

the number and size of the placental form of gluthatione-S-tranferase in the liver as well as

354

hepatocyte nodules and foci.28 It was concluded that prior exposure to AFB1 increased the

355

cancer potency of FB1 and the combined mycotoxins may show synergistic interaction in cancer

356

initiation and promotion.28 Orsi et al. 97 also reported a synergistic interaction as significant

357

body weight loss and differences in liver and kidney weight in White New Zealand rabbits orally

358

administrated with AFB1 and FB1.97 Increased AST, ALT, urea and creatinine were also

359

observed indicating hepatic and renal injury when combined mycotoxins were treated.97 In

360

another study,98 pronounced apoptosis and mitotic hepatocyte, increased number of apoptotic

361

tubular epithelial cells in kidney and lymphocytic infiltrates in small intestine were observed in

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rats treated with AFB1 and FB1 in combination. Moreover, AFB1 + FB1 induced increased Sa

363

and Sa/So ratio in kidney and liver, suggesting AFB1 may enhance FB1-induced impairments of

364

sphingolipid metabolism in those organs.98 As we mentioned above, due to FB1 inhibits

365

sphingolipid biosynthesis from Sa to So, in consistence, elevated Sa levels as well as the Sa/So

366

ratio are observed. The combined effects of AFB1 and FB1 on immunotoxicity and genotoxicity

367

have been studied using in vitro and in vivo models99-100 based on a hypothesis of their

368

mechanism is closely related to ROS generation.101-102 Mary et al. 100 reported that combination

369

of AFB1 and FB1 increased total ROS and oxidation of biomolecules most significantly in spleen

370

mononuclear cells from Wistar rats while treatments with individual mycotoxins also showed

371

similar effects. However, superoxide anion radical was increased only when the cells were

372

treated with both mycotoxins, suggesting the synergism on oxidative damage due to its stronger

373

pro-oxidant action.100 Increased ROS generation was also observed in the spleen isolated from

374

Balb/c mice fed AFB1 and FB1 individually or in combination.99 Moreover, AFB1 and FB1

375

exposure in combination resulted in decreased SOD, increased IL-4 and IL-10, decreased IFN-γ

376

and TNF-α, and increased level of apoptotic DNA (sub-G1 population).99

377

While there are few reports regarding DON-induced kidney toxicity,103 Lei et al. 104 and

378

Sun et al. 105 performed the individual and combined cytotoxic effects of AFB1 and DON or ZEN

379

using porcine kidney 15 cells (PK-15) and BRL 3A rat liver cells, respectively. Combined

380

mycotoxins of AFB1 + ZEN and AFB1 + DON showed synergistic effects,104 as individual

381

treatments of AFB1 or DON induced ROS production and apoptosis significantly while ZEN had

382

no effect on apoptosis but only slightly induced ROS production.104 In addition, when AFB1 +

383

ZEN was treated, different ZEN doses ameliorated the ROS production induced by 1 µM of

384

AFB1, but 10 µM of ZEN promoted the ROS production caused by 5 and 10 µM of AFB1.104 In

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the study by Sun et al. 105, the synergistic interaction between AFB1 + ZEN and AFB1 + DON

386

were observed in cytotoxicity, however, when the cells were exposed to these mycotoxins

387

individually, only AFB1 + DON induced intracellular ROS production and promoted apoptosis in

388

the BRL 3A rat liver cells. Additionally, the authors demonstrated that AFB1 + DON upregulate

389

the oxidative stress and apoptotic genes Hsp70, p53, Bax, caspase-3, and caspase-8, along with

390

downregulation of the antiapoptotic gene Bcl-2 Sun et al. 105. The authors concluded that the

391

synergistic cytotoxicity of the combination is caused by inducing ROS production and promoting

392

apoptosis.105

393

Interactions between OTA and Fusarium mycotoxins

394

OTA is one of the most studied mycotoxins in recent years due to its presence in a wide

395

range of food commodities including processed food products, such as wine, beer, and roasted

396

coffee beans as well as cereal grains. OTA is often found in cereals and cereal derived food

397

products together with AFs, FBs, DON, and ZEN. Both OTA and FB1 are nephrotoxic and

398

hepatotoxic; thus a number of studies have shown additive or synergistic effects for endpoints

399

related to the nephrotoxicity and hepatotoxicity. In addition to its nenephrotoxicity, FB1 can acts

400

as a promoter in carcinogenesis and potentiate OTA genotoxicity and carcinogenicity.106-107

401

The combined effects of OTA and FB1 have been reported to be additive or

402

synergistic.106, 108-114 Synergism between OTA and FB1 in cytotoxicity was observed in human

403

lymphocytes and intestinal cells, monkey kidney cells, rat brain glioma cells.112-113 According to

404

Šegvić Klarić et al. 111, subcytotoxic concentration of OTA and FB1 showed additive effect when

405

the two toxins were added to porcine kidney epithelial cells (PK15) as determined by increased

406

cytotoxicity, lipid peroxidation, and decreased GSH level.111 Additional studies conducted by

407

the same group showed additive interaction on LDH activity and apoptosis index and synergistic

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interaction on caspase-3 activity in combined treatment with OTA and FB1110 as well as an

409

additive genotoxic effect by increased the frequency of micronuclei and nucleoplasmic

410

bridges.109 More recently, FB1 was found to induce increased permeability of vessels and slight

411

to moderate degenerative changes in the kidneys in addition to the typical damages caused by

412

OTA, i.e. strong degenerative changes in proximal tubules and fibrosis.108 The mixture of OTA

413

and FB1 also caused stronger legions in kidney and more pronounced changes in biochemical

414

parameters including AST, ALT, total protein, and albumin, and disturbances in humoral

415

immune response.108

416

While OTA’s mechanism of toxicity is not understood clearly, it is known that OTA and

417

FB1 produce ROS with subsequent oxidative damage.115-117 It is also known that ROS may

418

directly and/or indirectly damage DNA through itself or its products.118 In an attempt to

419

elucidate the mechanism of toxicity with rats, Domijan et al. 114 showed that OTA and FB1

420

induced DNA damage in the kidneys synergistically, indicating that beside oxidative stress some

421

other mechanism is also involved in their genotoxic effect.114 Later Hadjeba-Medjdoub et al. 106

422

demonstrated that FB1 promotes OTA-specific DNA adducts using human kidney cell lines

423

(HK2), including C-C8dG OTA and OTHQ-related adducts that are found in human urothelial

424

tumors in the EN areas. It is unclear how OTA may interact with ZEN as one group reported

425

additive119 while the other observed antagonistic 120 when the cytotoxicity was measured in the

426

HepG2 cells. Although OTA and ZEN may not likely to occur in the same commodity

427

simultaneously, their potential interaction needs to be understood more clearly as they may

428

contribute to the burden from difference sources of diet.

429

Interactions between Fusarium mycotoxins

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Despite the high occurrence of mycotoxins from Fusarium spp., only a limited number of

431

studies on combined toxicity of Fusarium mycotoxins are available mainly focused on their

432

cytotoxicity and immunosuppression. For the interaction between FB1 and ZEN, Tajima et al. 59

433

showed dose-dependent inhibitory effects of ZEN while FB1 induced cell proliferation in a DNA

434

synthesis inhibition assay using a mouse fibroblast cell line (L939) suggesting no direct

435

interaction between the two mycotoxins. Kouadio et al. 121, however, observed varying

436

responses of antagonism in cytotoxicity, less than additive in DNA synthesis, and additive in

437

DNA fragmentation and lipid peroxidation.

438

Combined toxicity of ZEN and other Fusarium toxins need to be interpreted with care

439

partly due to the mechanism of ZEN is unique, i.e. estrogenic activity rather than other adverse

440

effects observed with the rest. As such, when ZEN and DON were combined, antagonism in

441

cytotoxicity assay using a human colon carcinoma cell line (HCT116) was observed possibly by

442

triggering the mitochondrial apoptotic process.122 Meanwhile, Ficheux et al. 123 reported additive

443

myelotoxic effect of DON + ZEN on the human granulo-monocytic hematopoietic progenitors

444

through apoptosis by the stimulation of caspase-3 activity as suggested earlier.124 These results

445

suggest that the toxicity of combined mycotoxins may not be predicted based on the mechanism

446

of individual toxins particularly when they do not share the common end point or mechanism.

447

FBs disrupts sphingolipid biosynthesis which is essential for the formation of cell

448

membranes, while DON inhibits protein synthesis by binding with ribosome.32, 125-126 When the

449

two mycotoxins are combined, DON and FBs have toxicities on the intestinal tract through

450

different mechanisms.32, 127 At low doses, about 3 mg/kg DON and 6 mg/kg FB1 + FB2, the liver

451

was significantly more affected in piglets after 5 weeks.128 In addition, mRNA expressions of

452

IL-8, IL-1β, IL-6, and macropharge inflammatory protein-1β were significantly decreased in the

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453

spleen upon exposure suggesting synergism between DON and FBs. However, a follow up study

454

using the same model, i.e. 5 week-old piglets, showed varying results, i.e. synergistic in immune

455

cells, additive in the expression of cytokines and junction protein, less than additive in cytokine

456

expression and histological lesions, and antagonistic in immune cells and cytokine expression.129

457

Variable interaction between DON and FBs were also reported by others,121, 123 which indicates

458

the complexity of interaction as well as the importance in selecting appropriate model system

459

and end point. It should also be noted that the experimental design including the doses of each

460

mycotoxins need to be considered carefully.

461 462

Significance of mycotoxins in infant/baby foods

463

It is of special interest for public health to review the occurrence of mycotoxins in foods

464

destined for infants and young children as they are vulnerable and sensitive population. Hence,

465

more stringent regulatory guidelines or maximum levels than those for general public have been

466

adopted in many countries to protect this particular population from potential exposure to major

467

mycotoxins. While the bulk of infant formulas on the market are made with cow’s milk, infant

468

foods such as infant cereals and snacks are largely cereal-based. As in the processed products in

469

general, mycotoxins present in the raw materials tends to remain in the final products. It may

470

also be noted that the occurrence and or the levels of mycotoxins in infant foods could be even

471

higher than that in other food product groups since most infant foods including infant cereals are

472

made of single grain rather than mixture of various sources. In addition, infants’ diet is mostly

473

rely on a limited variety of foods during the gradual replacement or transition from exclusive

474

milk feeding beyond the first few months of infancy, resulting in increased risk upon exposure to

475

mycotoxins.

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Surveillance studies focusing on the occurrence of mycotoxins in infant foods are scarce.

477

Hence, effort was made to extract relevant data from additional literature documented

478

mycotoxins in cereals based foods (Table 4). In general, the occurrence of AFs is low and less

479

consistent than other mycotoxins while the levels as high as 5.6 µg/kg was found in rice-based

480

infant cereals from the U.S. Based on the few surveys available, FBs and ZEN are not likely of

481

concern with low incidence and concentrations, which may be attributed to the limited use of

482

maize, where these two mycotoxins are commonly associated, in manufacturing infant cereals.

483

On the other hand, OTA and DON showed significant levels of contamination. The

484

incidences of OTA were similar when the two regions are compared, i.e. 26% and 30% in

485

Europe and Americas, respectively, while the levels of contamination detected in the samples

486

from the U.S. tend to be much higher than those from European countries. It would be of

487

interest to note that oat-based infant cereals showed the highest incidence and concentration

488

among all sample groups with up to 22.1 µg/kg. According to Meucci et al. 130, AFM1 was

489

found in only two samples at levels below EU limit of 25 ng/L among the 185 samples of infant

490

formula in Italy while OTA was detected in 72% (133/185) samples in the range of 35 – 689

491

ng/L. This level of contamination represents the prevalence of OTA in infant foods that may

492

exceed a suggested tolerable daily intake (TDI) of 5 ng/kg b.w./day for infants and young

493

children131 or negligible cancer risk intake (NCRI) of 4 ng/kg b.w./day.132

494

DON may be considered as another significant concern. In 2011, Cano-Sancho et al. 133

495

reported that infants were the most exposed groups in Spain, among Catalonian population in

496

particular, exceeding the TDI of 1 µg/kg b.w. established by the European Commission

497

Scientific Committee on Food (SCF)134 and the Joint FAO/WHO Expert Committee on Food

498

Additives (JEFCA).135 Although it is somewhat dated, Lombaert et al. 136 conducted a survey

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499

with a total of 363 infant cereals in Canada including 273 samples of North American and 90

500

European origins. Among the mycotoxins analyzed, DON was found most frequently with 63%

501

(150/237) of incidence and a maximum concentration of 980 µg/kg. While barley-based

502

products were most consistently contaminated with DON (29/50 or 58% with 260 µg/kg mean

503

positive), OTA was also detected in 10 samples out of 41 (21%) with a mean positive

504

concentration of 1.00 µg/kg. It was also noted that multi-grain cereals (62/86 or 60% with 116

505

µg/kg mean positive) also showed high level of DON contamination. Together with DON and

506

OTA, other major mycotoxins including FBs and ZEN were also detected in the samples

507

reinforcing the significance of co-occurrence of mycotoxins in cereal-based foods.

508

Meanwhile, Rubert et al. 137 analyzed 21 mycotoxins in 35 baby foods from Spain and

509

found OTA, FBs, DON, and ZEN with DON being the most common in the range of 70 – 210

510

µg/kg prompting the needs of further studies in co-occurrence of mycotoxins. In addition to the

511

five major mycotoxins discussed in this review, it would be worth noting that other mycotoxins

512

from a variety of commodities and food products may add the burden particularly for infants and

513

young children. For instance, multiple trichothecenes such as T-2 toxin, HT-2 toxin, and

514

nivalenol tend to co-contaminate cereal grains along with DON. Hence, considering possible

515

interaction among the multiple trichothecenes would be plausible in considering their close

516

structure-toxicity relationship. Bonerba et al. 138 detected 9 µg/kg of patulin in 22 samples out of

517

120 homogenized fruit-based baby food products collected in Italy. This level was below the

518

limit of 10 µg/kg in baby food set by JECFA 139 based on a PMTDI of 0.4 µg/kg b.w.139 but

519

indicates the needs of continued monitoring. Lesser known mycotoxins such as beauvericin,

520

enniatins, and fusaproliferin have appeared in the literature prompting further research140-141

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521

while tenuazonic acid in infant food particularly those made of sorghum was suggested potential

522

health hazards.142

523 524 525

Conclusion Based on the worldwide occurrence of mycotoxins in various agricultural crops and food

526

products, it may be assumed that human is often, if not constantly, exposed to mycotoxins. It is

527

also realistic to consider the risk of exposure to multiple mycotoxins due to the nature of fungal

528

and mycotoxin contamination as well as the diverse sources of mycotoxins in our diet.

529

Traditionally, however, toxicological studies and risk assessments have been carried out for

530

individual mycotoxins especially for those major mycotoxins of AFs, OTA, FB1, DON, and ZEN

531

and more. Thus regulations, which have direct impact on public health, followed similar steps of

532

risk assessment with similar data sets available. It seems that mycotoxins may interact with each

533

other to cause adverse effects that we may or may not predict. While certain combination or co-

534

exposure can result in additive or synergistic, their interaction could also be antagonistic or non-

535

interactive. Hence, referring a given combination as “synergistic” without a solid evidence

536

should be cautioned to avoid potential misconception or misunderstanding.

537

Although it was not discussed in this review, masked- or bound mycotoxins should be

538

considered in risk assessment. Efforts have been made in recent years to better understand the

539

significance of these conjugated forms of mycotoxins including their occurrence, bioavailability

540

and level of exposure. Needless to mention, chemical or instrumental analyses and

541

characterization is absolutely critical in laying out the groundwork. However, there are also

542

challenges and limitations in investigating masked mycotoxins including those masked forms are

543

hard to extract, can be lost during the clean-up process, and the standards are not commercially

25 ACS Paragon Plus Environment

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544

available. Therefore, bioassays, either in vitro or in vivo, would be useful to assess toxicity of

545

multiple- or masked mycotoxins, which will lead us to more accurate risk assessment to protect

546

public health.

547

Scientific evidences exist to prove significance of combined exposure and importance of

548

co-occurrence of mycotoxins. Hence, greater effort should be made to investigate the combined

549

risk of multiple mycotoxin exposure following accurate dose-response relationships and

550

toxicological endpoints. It is also important to continue and expand, if possible, surveillance and

551

biomonitoring program to properly understand the changing dynamics of toxigenic fungi and

552

mycotoxin contamination as well as monitoring the level of exposure in humans in reality.

553

Future research may expand to include other relevant mycotoxins, e.g. citrinin and

554

trichothecenes other than DON, or combinations of those emerging and lesser-known

555

mycotoxins.

556 557

Acknowledgements

558

This project was supported in part by Agriculture and Food Research Initiative

559

Competitive Grant No. 2011-67005-20676 and 2016-67017-24418 from the USDA National

560

Institute of Food and Agriculture.

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Kabak, B. Ochratoxin A in cereal-derived products in Turkey: occurrence and exposure assessment. Food Chem. Toxicol. 2009, 47 (2), 348-352. Raiola, A.; Meca, G.; Mañes, J.; Ritieni, A. Bioaccessibility of deoxynivalenol and its natural co-occurrence with ochratoxin A and aflatoxin B1 in Italian commercial pasta. Food Chem. Toxicol. 2012, 50 (2), 280-287. Vidal, A.; Marín, S.; Ramos, A. J.; Cano-Sancho, G.; Sanchis, V. Determination of aflatoxins, deoxynivalenol, ochratoxin A and zearalenone in wheat and oat based bran supplements sold in the Spanish market. Food Chem. Toxicol. 2013, 53, 133-138. Pleadin, J.; Vahčić, N.; Perši, N.; Ševelj, D.; Markov, K.; Frece, J. Fusarium mycotoxins' occurrence in cereals harvested from Croatian fields. Food Control 2013, 32 (1), 49-54. Stanković, S.; Lević, J.; Ivanović, D.; Krnjaja, V.; Stanković, G.; Tančić, S. Fumonisin B1 and its co-occurrence with other fusariotoxins in naturally-contaminated wheat grain. Food Control 2012, 23 (2), 384-388. Silva, L.; Fernández-Franzón, M.; Font, G.; Pena, A.; Silveira, I.; Lino, C.; Mañes, J. Analysis of fumonisins in corn-based food by liquid chromatography with fluorescence and mass spectrometry detectors. Food Chem. 2009, 112 (4), 1031-1037. Dall'Asta, C.; Galaverna, G.; Mangia, M.; Sforza, S.; Dossena, A.; Marchelli, R. Free and bound fumonisins in gluten‐free food products. Mol. Nutr. Food Res. 2009, 53 (4), 492499. Ariño, A.; Juan, T.; Estopañan, G.; González-Cabo, J. F. Natural occurrence of Fusarium species, fumonisin production by toxigenic strains, and concentrations of fumonisins B1 and B2 in conventional and organic maize grown in Spain. J. Food Prot. 2007, 70 (1), 151-156. Silva, L.; Lino, C.; Pena, A.; Moltó, J. C. Occurrence of fumonisins B1 and B2 in Portuguese maize and maize-based foods intended for human consumption. Food Addit. Contam. 2007, 24 (4), 381-390. Lino, C.; Silva, L.; Pena, A.; Fernández, M.; Mañes, J. Occurrence of fumonisins B1 and B2 in broa, typical Portuguese maize bread. Int. J. Food Microbiol. 2007, 118 (1), 79-82. Cerveró, M. C.; Castillo, M.; Montes, R.; Hernández, E. Determination of trichothecenes, zearalenone and zearalenols in commercially available corn-based foods in Spain. Rev. Iberoam. Micol. 2007, 24 (1), 52. Jajić, I.; Jurić, V.; Abramović, B. First survey of deoxynivalenol occurrence in crops in Serbia. Food Control 2008, 19 (6), 545-550. Castillo, M.Á.; Montes, R.; Navarro, A.; Segarra, R.; Cuesta, G.; Hernández, E. Occurrence of deoxynivalenol and nivalenol in Spanish corn-based food products. J. Food Compost. Anal. 2008, 21 (5), 423-427. Malachova, A.; Dzuman, Z.; Veprikova, Z.; Vaclavikova, M.; Zachariasova, M.; Hajslova, J. Deoxynivalenol, deoxynivalenol-3-glucoside, and enniatins: the major mycotoxins found in cereal-based products on the Czech market. J. Agric. Food Chem. 2011, 59 (24), 12990-12997. Ibáñez-Vea, M.; Lizarraga, E.; González-Peñas, E.; de Cerain, A. L. Co-occurrence of type-A and type-B trichothecenes in barley from a northern region of Spain. Food Control 2012, 25 (1), 81-88. Rodríguez-Carrasco, Y.; Berrada, H.; Font, G.; Mañes, J. Multi-mycotoxin analysis in wheat semolina using an acetonitrile-based extraction procedure and gas chromatography–tandem mass spectrometry. J. Chromatogr. A 2012, 1270, 28-40. 40 ACS Paragon Plus Environment

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1194 1195 1196 1197 1198 1199 1200 1201 1202 1203 1204 1205 1206 1207 1208 1209 1210 1211 1212 1213 1214 1215 1216 1217 1218 1219 1220 1221

Journal of Agricultural and Food Chemistry

230.

231.

232.

233. 234.

235. 236.

237.

238. 239. 240.

Uhlig, S.; Eriksen, G. S.; Hofgaard, I. S.; Krska, R.; Beltrán, E.; Sulyok, M. Faces of a changing climate: semi-quantitative multi-mycotoxin analysis of grain grown in exceptional climatic conditions in Norway. Toxins 2013, 5 (10), 1682-1697. Lindblad, M.; Gidlund, A.; Sulyok, M.; Börjesson, T.; Krska, R.; Olsen, M.; Fredlund, E. Deoxynivalenol and other selected Fusarium toxins in Swedish wheat—Occurrence and correlation to specific Fusarium species. Int. J. Food Microbiol. 2013, 167 (2), 284-291. Rodríguez-Carrasco, Y.; Moltó, J. C.; Berrada, H.; Mañes, J. A survey of trichothecenes, zearalenone and patulin in milled grain-based products using GC–MS/MS. Food Chem. 2014, 146, 212-219. Manova, R.; Mladenova, R. Incidence of zearalenone and fumonisins in Bulgarian cereal production. Food Control 2009, 20 (4), 362-365. Cano-Sancho, G.; Marin, S.; Ramos, A.; Sanchis, V. Occurrence of zearalenone, an oestrogenic mycotoxin, in Catalonia (Spain) and exposure assessment. Food Chem. Toxicol. 2012, 50 (3), 835-839. Engelhardt, G.; Barthel, J.; Sparrer, D., Fusarium mycotoxins and ochratoxin A in cereals and cereal products. Mol. Nutr. Food Res. 2006, 50 (4‐5), 401-405. Zinedine, A.; Blesa, J.; Mahnine, N.; El Abidi, A.; Montesano, D.; Mañes, J. Pressurized liquid extraction coupled to liquid chromatography for the analysis of ochratoxin A in breakfast and infants cereals from Morocco. Food Control 2010, 21 (2), 132-135. Vendl, O.; Crews, C.; MacDonald, S.; Krska, R.; Berthiller, F. Occurrence of free and conjugated Fusarium mycotoxins in cereal-based food. Food Addit. Contam. 2010, 27 (8), 1148-1152. Alvito, P. C.; Sizoo, E. A.; Almeida, C. M.; van Egmond, H. P. Occurrence of aflatoxins and ochratoxin A in baby foods in Portugal. Food Anal. Methods 2010, 3 (1), 22-30. Juan, C.; Raiola, A.; Mañes, J.; Ritieni, A. Presence of mycotoxin in commercial infant formulas and baby foods from Italian market. Food Control 2014, 39, 227-236. Ozden, S.; Akdeniz, A. S.; Alpertunga, B. Occurrence of ochratoxin A in cereal-derived food products commonly consumed in Turkey. Food Control 2012, 25 (1), 69-74.

1222 1223

1224

41 ACS Paragon Plus Environment

Journal of Agricultural and Food Chemistry

Figure captions Figure 1. Flowchart for mycotoxins in food chain. Figure 2. Chemical structure of mycotoxins. (A) aflatoxin B1 (AFB1), (B) ochratoxin A (OTA), (C) fumonisin B1 (FB1), (D) deoxynivalenol (DON), and (E) zearalenone (ZEN). Figure 3. Various factors may be influenced on interactions of mycotoxins on in vitro or in vivo toxicity.

42 ACS Paragon Plus Environment

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Page 43 of 53

Journal of Agricultural and Food Chemistry

Table 1. Summary of the major mycotoxins, associated fungi, examples of optimal conditionsa for major mycotoxins production, and its physiological effects.

Mycotoxins

Fungi

Temperature (°C) 33

Water activity (aw) 0.99

Aflatoxins

Aspergillus flavus and A. parasiticus

Fumonisins

Fusarium verticillioides and F. proliferatum

10 - 30

Ochratoxins

A. ochraceus A. carbonarius Penicillium verrucosum

Trichothecenes (Deoxynivalenol)

F. sporotrichioides, F. graminearum, F. culmorum, F. roseum, F. tricinctum, F. acuminatum F. graminearum

Zearalenone a

Toxicity

References

Carcinogenic, acute hepatotoxic, immunology suppression

6, 143-146

0.93

Carcinogenic, hepatotoxic

6, 147-148

30 15 - 20 25

0.98 0.85 - 0.90 0.90 - 0.98

Cacinogenic, nephrotoxic, hepatotoxic, teratogenic

6, 17-20, 149-152

15 - 25

0.97 - 0.99

Gastrointestinal haemorrhaging, immunodepressants

153-156

25 - 30

0.98

Estrogenic activity

157-158

The majority of data generated on environmental optima for mycotoxin production was obtained from cultured rather than actual field

or storage environment.

43 ACS Paragon Plus Environment

Journal of Agricultural and Food Chemistry

Page 44 of 53

Table 2. European regulations and the U.S. Food and Drug Administration (FDA) action levels for major mycotoxins in cereals and cereal derived food products for human conception 7-9, 35, 159-160.

European regulation

Mycotoxins Aflatoxns

Commodity Cereals and processed cereal products except corn and rice Corn and rice Cereal based baby foods for infants and young children

Ochratoxins Unprocessed cereals All product derived from unprocessed cereals intended for direct consumption Cereal based baby foods for infants and young children Fumonisins Unprocessed corn Corn grits, meal, and flour Corn-based breakfast cereals and corn-based snacks Processed corn-based baby foods for infants and young children Deoxynivalenol Durum wheat, oats, and corn Unprecessed cereals other than durum wheat, oats, and corn Cereal flours used as raw material in food products Cereal products as consumed and other cereal based products as retail stage Cereal based baby foods for infants and young children Zearalenone Unprecessed cereals other than corn Unprocessed corn Cereal flours other than corn flour 44 ACS Paragon Plus Environment

Maximum limit (µg/kg) AFB1 Total AFsa 2 4 5 10 0.1 OTA 5 3 0.5 Sum of FB1 and FB2 4,000 1,000 800 200 DON 1,750 1,250 750 500 200 ZEN 100 350 75

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Journal of Agricultural and Food Chemistry

Corn flour All product derived from unprocessed cereals intended for direct consumption (excluding processed corn-based foods) Corn intended for direct human consumption, corn- based snacks and corn-based breakfast cereals Cereal based baby foods (including processed corn-based foods) for infants and young children The U.S. FDA action levels

Fumonisins Degermed dry milled corn products (corn grits, meal, and flour) Cleaned corn intended for popcorn Dry milled corn bran Cleaned corn intended for masa production Deoxynivalenol

a

Processed wheat-based products Total AFs means sum of AFB1, AFB2, AFG1, and AFG2.

b

Total fumonisins means sum of FB1, FB2, and FB3.

45 ACS Paragon Plus Environment

200 50 100 20 Total fumonisinsb 2,000 - 4,000 3,000 4,000 4,000 DON 1,000

Journal of Agricultural and Food Chemistry

Page 46 of 53

Table 3. Occurrence of mycotoxins in cereal grains and cereal-based derived food products.

Aflatoxins Food Commodity Raw

Barley Corn Rice

Africa

Wheat Others Total Processed

Other-based Total

Raw

Corn Rice

America

Processed

NAa

NA

52/108 (48%) 130/243 (53%) 23/50 (46%)

20 - 1,642

2/13 (15%)

1.7 - 3.0

207/414 (50%) 27/27 (100%) 27/27 (100%) 35/231 (15%) NA

0.1 - 20

0-7

0 - 1,642 4.3 1,138.8 4.3 1,138.8

Incidence (%) 52/123 (42%) 25/128 (20%) 155/403 (38%) 52/147 (35%) 43/113 (38%) 327/914 (36%)

Fumonisins

Deoxynivalenol

Incidence (%)

Range (µg/kg)

Incidence (%)

Range (µg/kg)

Incidence (%)

Range (µg/kg)

0.01 - 940

NA

NA

NA

NA

NA

NA

0.13 - 7.22

83/107 (78%)

0.05 24,225

76/77 (98%)

18 - 435

0 - 1,164

3/31 (10%)

0.4 - 4.4

5/21 (24%)

0 - 112.2

NA

117/164 (71%)

7.2 - 303

0.01 - 250

NA

NA

NA

NA

4/17 (24%)

7.3 - 14.0

0 - 1,164

198/262 (76%)

0 - 435

367/625 (59%)

0 - 1,169

NA

NA

NA

NA

NA

NA

NA

NA

-b

-

-

-

-

-

-

-

220/231 (95%)

4/21 (19%)

160 - 834

11/23 (48%)

25 - 2,565

NA

NA

NA

206 - 4,732

NA

NA

160 - 4,732

11/23 (48%)

25 - 2,565

NA

NA

NA

20 - 420

7/34 (21%)

3.0 - 21.0

20 - 80

3/27 (11%)

3.0 - 6.9

40

2/29 (7%)

3.0 - 3.6

NA

NA

13/31 (42%)

0 - 12.5

15 - 34,700

NA

NA

NA

29/30 (97%) 249/261 (95%)

10.5 1,245.7 10.5 34,700

75/113 (66%) 79/134 (59%) NA

NA

Total

35/231 (15%)

0.2 - 1,393

13/31 (42%)

0 - 12.5

Barley-based

NA

NA

NA

NA

NA

NA

Corn-based

31/45 (69%)

0.002 0.818

0.05 - 1.2

30/34 (88%)

10 - 1,980

0.05 - 9.3

5/19 (26%)

10 - 57

0.05 - 0.46

2/29 (7%)

5

0.05 - 2.1

5/29 (17%)

10 - 51

Oat-based

NA

NA

Rice-based

12/24 (50%)

Wheat-based

2/48 (4%)

0.002 0.109 0.008 0.020 0.002 0.255 0.002 0.818

57/167 (34%) 159/230 (69%) 12/95 (13%) 75/183 (41%) 11/30 (37%) 314/705 (45%)

0.26 - 12.6

6/28 (21%)

0.18 - 2.84

8/17 (47%)

0.26 - 97.7

0.15 - 850

6/30 (20%)

0.10 - 5.76

457/626 (73%)

0 - 71,121

Corn

0 - 560

0.05 24,225

NA

0.05 - 1.0 0.05 - 9.3

11/24 (46%) 53/135 (39%)

10 - 88 5 - 1,980

12/34 (35%) 17/27 (63%) 1/29 (3%) 21/29 (72%) 21/37 (57%) 72/156 (46%) 14/42 (33%) 41/124 (11%)

46 ACS Paragon Plus Environment

20 - 940 20 - 770 20 - 940

11/29 (38%) 11/37 (30%) 34/156 (22%)

42, 161-174

0 - 1,169

NA

0.2 - 1,393

Reference

0.2 - 309

86/138 (62%)

NA

Barley

79/128 (62%) 114/243 (47%) 170/237 (72%)

8 - 950

NA

42/55 (76%) 87/172 (51%) 12/27 (44%) 223/342 (65%)

Zearalenone

Range (µg/kg)

NA

Total Asia

Range (µg/kg)

Wheat

Other-based

Raw

Ochratoxin A

Incidence (%)

44-45, 175-183

3.0 - 5.5 3 - 100 3 - 100

5.5 - 530

6/17 (35%)

1.0 - 20.3

10 - 2,625

5/75 (7%)

1.0 - 1,250

46, 184-203

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Journal of Agricultural and Food Chemistry

Oat Rice Wheat

Processed

0.20 - 15.5 2.0 - 9.4

Total

1,272/2,019 (63%)

0.1 - 850

Barley-based

NA

NA

Corn-based

12/96 (13%)

Oat-based

6/15 (40%) 62/340 (18%) 13/40 (33%) 25/61 (41%) 118/514 (23%)

0.10 - 0.20 0.08 - 4.34 0.15 - 2.11

7/15 (47%) 43/150 (29%) 74/122 (61%)

0.12 - 177.3 0 - 500 0.20 - 155

6/15 (40%) 21/90 (23%) 219/326 (67%)

6.7 - 100 6.2 - 81.2 5.5 - 41,157

0/15 (0%) 17/90 (19%) 33/220 (15%)

1.5 - 51.1 10.1 - 3,049

0.01 - 2.59

6/30 (20%)

2.0 - 6.5

NA

NA

NA

NA

0.01 - 5.76

595/960 (62%)

0 - 17,121

301/597 (50%)

5.5 - 41,157

61/417 (15%)

1.0 - 3,049

NA

NA

0/60 (0%)

-

NA

NA

NA

NA

0.15 - 8.95

6/178 (3%)

0.10 - 5.14

196/677 (29%)

0.15 - 1,670

29/34 (85%)

6.2 - 348

3/8 (38%)

1.0 - 13.5

5/10 (50%)

0.65 - 2.85

9/74 (12%)

0.01 - 2.50

NA

NA

NA

NA

NA

NA

Rice-based

9/13 (69%)

0.68 - 3.79

0/21 (0%)

-

NA

NA

NA

NA

NA

NA

Wheat-based

25/30 (83%)

0.1 - 5.07

0.1 - 1

13/16 (81%)

0 - 400

357/446 (80%)

0.9 - 791

5/311 (2%)

1.4 - 35.0

Other-based

0/51 (0%)

-

0.01 - 1.79

0/95 (0%)

-

NA

NA

NA

NA

0.01 - 5.14

209/848 (25%)

0 - 1,670

0.9 - 791

8/319 (3%)

1.0 - 35.0

0.013 - 0.17

5/34 (15%)

25 - 121

Barley

51/251 (20%) 112/112 (100%)

0.1 - 8.95 0.015 - 0.34

103/210 (49%) 136/232 (59%) 254/715 (36%) 64/120 (53%)

386/480 (80%) 150/178 (84%) 73/153 (48%) 35/61 (57%)

0 - 1,111

68/184 (37%) 53/82 (65%) 28/60 (47%)

0.3 - 1,340

Corn

1/14 (7%)

1.6

0/14 (0%)

-

72/148 (49%)

25 - 4,438

Oat

NA

NA

NA

NA

2/33 (6%)

25 - 31

0.45 - 33

12/183 (7%)

1.0 - 75

2/100 (2%)

-

3/100 (3%)

71 - 176

NA

NA

28 - 5,400

283/414 (68%)

0.6 - 6,460

213/361 (59%)

5 - 678

Wheat

Europe

0.1 - 308

3/10 (30%)

Rice

Processed

992/1565 (63%) 34/60 (57%)

0.12 - 1.94

Others

Total Raw

8/15 (53%)

26/181 (9%) 23/62 (37%)

0.01 - 0.144

7/91 (8%)

0 - 2.94

114/175 (65%)

0.04 - 2,942 34 - 7,230

10 - 611 4 - 1,670

Others

0/2 (0%)

-

4/29 (14%)

0 - 0.038

0/5 (0%)

-

4/27 (15%)

0 - 240

NA

NA

Total

162/371 (44%)

0.01 - 33

87/437 (20%)

0 - 75

195/495 (39%)

25 - 5,400

548/933 (59%)

0 - 7,230

362/687 (53%)

0.3 - 1,670

Barley-based

1/4 (25%)

24

0/4 (0%)

-

0/4 (0%)

-

0/4 (0%)

-

NA

NA

20 - 3,310

69/248 (28%)

1.3 - 195

57/287 (20%)

0.7 - 145

Corn-based

4/43 (9%)

0.05 - 0.13

1/52 (2%)

0.06 - 0.10

72/185 (39%)

Oat-based

0/6 (0%)

-

6 /39 (15%)

0.2 - 0.4

0/6 (0%)

-

6/47 (13%)

100 - 276

5/41 (12%)

2 - 25

Rice-based

0/21 (0%)

-

0/24 (0%)

-

0/21 (0%)

-

3/47 (6%)

1.3 - 5.5

0/26 (0%)

-

Wheat-based

55/179 (31%)

0.05 - 66.7

0.06 - 112

2/65 (3%)

83 - 184

Other-based

1/35 (3%)

6.4

0.02 - 1.84

0/20 (0%)

-

106/241 (44%) 77/157 (49%)

158/278 (57%) 100/159 (63%)

47 ACS Paragon Plus Environment

1.3 - 6,178 1.25 - 594

19/224 (8%) 54/195 (28%)

0.7 - 39 0.65 - 20.9

12, 204-234

Journal of Agricultural and Food Chemistry

Total Raw

Barley Corn Oat Rice

Global

Wheat

Processed

0.015 - 12.6

8/15 (53%)

0.12 - 1.94

1,148/1,989 (58%) 80/172 (47%)

0.05 - 66.7

0.1 - 1,393

0.1 - 1,642 0 - 15.5

Others

5/25 (20%)

Total

1,676/3,035 (55%)

0 - 1,642

Barley-based

1/4 (25%)

24

Corn-based

47/184 (26%)

0.002 - 8.95

Oat-based

5/16 (31%)

0.65 - 2.85

Rice-based Wheat-based Other-based Total

a

61/288 (21%) 124/139 (89%) 311/695 (45%)

21/58 (36%) 82/257 (32%) 70/168 (42%)

1.7 - 9.4

6/15 (40%) 242/957 (25%) 72/278 (26%) 72/203 (35%) 545/1,896 (29%) 0/4 (0%)

0.002 1,138.8

64/397 (16%) 174/343 (51%) 12/140 (9%) 284/634 (45%) 224/419 (53%)

0.002 1,138.8

758/1,937 (39%)

0.002 - 3.79 0.008 - 66.7

226/687 (33%)

190/517 (37%) 122/271 (45%) 31/172 (18%)

0.02 - 112 0.01 - 940 0.10 - 7.22 0.10 - 0.20 0 - 1,164 0 - 250

74/301 (25%) 13/51 (25%) 832/1,112 (75%) 9/48 (19%) 48/281 (17%) 217/327 (66%)

20 - 3,310 0.26 - 121 0 - 71,121 0.12 - 177.3 0 - 500 0.20 - 5,400

336/783 (43%) 164/220 (75%) 194/375 (52%) 41/76 (54%) 29/211 (14%) 694/1,017 (68%)

Page 48 of 53

1.25 - 6,178 0 - 1,111 0.04 - 2,942 6.7 - 7,230 0 - 176 0.6 - 41,157

135/773 (17%) 74/201 (37%) 148/308 (48%) 28/75 (37%) 131/333 (39%) 416/818 (51%)

0.65 - 145 0.3 - 1,340 0.2 - 2,565 4 - 1,670 0 - 1,169 0 - 3,049

0 - 950

6/35 (17%)

2.0 - 6.5

4/27 (15%)

0 - 240

4/17 (24%)

7.3 - 14.0

0 - 1,164

1,125/1,854 (61%)

0 - 71,121

1,126/1,926 (58%)

0 - 41,157

801/1,752 (46%)

0 - 3,049

-

0/64 (0%)

-

0/4 (0%)

-

NA

NA

0.05 - 5.14

298/896 (33%)

0.15 - 3,310

1.3 - 420

67/329 (20%)

0.7 - 145

0.01 - 9.3

5/25 (20%)

10 - 57

20 - 276

8/68 (12%)

2 - 25

0.05 - 0.46

2/50 (4%)

5

1.3 - 40

2/55 (4%)

3.0 - 3.6

0.05 - 112 0.01 - 1.84 0.01 - 112

20/110 (18%) 11/139 (8%) 336/1,284 (26%)

0 - 400 10 - 88 0 - 3,310

110/316 (35%) 23/74 (31%) 4/76 (5%) 536/753 (71%) 121/196 (62%) 794/1,419 (56%)

NA, not applicable. b-, no sample.

48 ACS Paragon Plus Environment

0.9 - 6,178 1.25 - 770 0.9 - 6,178

35/564 (6%) 65/232 (28%) 177/1,248 (14%)

0.7 - 39 0.65 - 100 0.65 - 145

Page 49 of 53

Journal of Agricultural and Food Chemistry

Table 4. Occurrence of mycotoxins in cereal-based infant/baby foods.

America

Asia

Food Commodity

Fumonisins

Deoxynivalenol

Incidence (%)

Range (µg/kg)

Incidence (%)

Range (µg/kg)

Wheat-based

NA

NA

NA

NA

NA

NA

Total

NA

NA

NA

NA

NA

NA

Balrey-based

3/35 (9%)

0.003 0.009

1/9 (11%)

14.4

1/8 (13%)

6.2

Corn-based

0/2 (0%)

-

NA

NA

NA

Oat-based

0/20 (0%)

-

30/51 (59%)

0.6 - 22.1

Rice-based

15/46 (33%)

0.002 - 5.9

2/54 (4%)

NA

NA

Wheat-based

Total

Europe

Ochratoxin A

Range (µg/kg)

Other-based

a

Aflatoxins Incidence (%)

44/104 (42%) 62/207 (30%)

Incidence (%) 98/110 (89%) 98/110 (89%)

Zearalenone

Range (µg/kg)

Incidence (%)

Range (µg/kg)

0.9 - 177

1/100 (1%)

4.2

0.9 - 177

1/100 (1%)

4.2

16/19 (84%)

3.6 - 125.6

0/8 (0%)

-

NA

NA

NA

NA

NA

0/20 (0%)

-

23/38 (61%)

2.5 - 146.5

9/20 (45%)

1.2 - 13.6

1.3 - 1.4

0/20 (0%)

-

7/20 (35%)

1.4 - 55.0

1/20 (5%)

9

2/6 (33%)

1.2

NA

NA

NA

NA

NA

NA

0.002 - 5.6

12/35 (34%)

1.0 - 5.9

0/16 (0%)

-

29/39 (74%)

4.4 - 106

3/16 (19%)

0.5 - 32.1

0.002 - 5.9

47/155 (30%)

0.6 - 22.1

1/64 (2%)

6.2

75/113 (66%)

1.4 - 146.5

13/64 (20%)

0.5 - 32.1

200

Barley-based

0/3 (0%)

-

1/3 (33%)

0.1

NA

NA

2/3 (67%)

1 - 108

0/3 (0%)

-

Corn-based

0/2 (0%)

-

2/2 (100%)

0.05

NA

NA

2/2 (100%)

1 - 103.8

0/2 (0%)

-

Oat-based

NA

NA

NA

NA

NA

NA

0/3 (0%)

-

0/3 (0%)

-

Rice-based

0/2 (0%)

-

4/17 (24%)

0.05 - 0.20

NA

NA

1/2 (50%)

40.2

0/2 (0%)

-

Wheat-based

0/18 (0%)

-

10/32 (31%)

0.05 - 0.12

NA

NA

14/21 (67%)

1 - 268

0/21 (0%)

-

Other-based

6/20 (30%)

21/91 (23%)

0.01 - 0.50

3/35 (9%)

75 - 100

9/35 (26%)

70 - 210

2/35 (6%)

10 - 15

Total

6/45 (13%)

38/145 (26%)

0.01 - 0.50

3/35 (9%)

75 - 100

28/66 (42%)

1 - 268

2/66(3%)

10 - 15

0.002 0.009 0.002 0.009

NA, not applicable. b-, no sample.

49 ACS Paragon Plus Environment

References

137, 214, 235240

45, 175, 178, 182

Journal of Agricultural and Food Chemistry

Figure 1.

50 ACS Paragon Plus Environment

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Journal of Agricultural and Food Chemistry

Figure 2.

51 ACS Paragon Plus Environment

Journal of Agricultural and Food Chemistry

Figure 3.

52 ACS Paragon Plus Environment

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Journal of Agricultural and Food Chemistry

ACS Paragon Plus Environment