A Food Toxicological Contemplation of Mycotoxins

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Peer-reviewed | Manuscript received: January 31, 2013 | Revision accepted: May 08, 2013

A food toxicological contemplation of mycotoxins

Pablo Steinberg, Hannover

Metabolism

Summary In order to become toxic, aflatoxin B1 Mycotoxins are the products of the endogenous metabolism of moulds that can must be metabolically activated v infest crops and already lead to adverse health effects in mammals and humans at ( Figure 3). Aflatoxin B1 is first me- low concentrations after the consumption of contaminated feed and food, re- tabolized to the aflatoxin B1-8,9- spectively. In the following report, the main mycotoxins detected in temperate epoxide in a cytochrome P450-cat- zones, namely aflatoxins, ochratoxin A, Fusarium mycotoxins (zearalenone, tri- alyzed reaction. Thereafter, the epox- 7 chothecenes and fumonisine), ergot alkaloids, patulin and citrinin, are briefly in- ide reacts with the N -position of troduced. In this context, their underlying mechanisms of toxicity, their main toxic guanine residues of the DNA and effects in humans and animals as well as the actual burden of foods with aflato- leads to the formation of the afla- 7 xins, ochratoxin A and Fusarium mycotoxins in Germany are described. toxin B1-N -guanine adduct. This adduct is chemically unstable and Keywords: Moulds, mycotoxins, aflatoxins, ochratoxin A, Fusarium toxins can be converted to the so-called

aflatoxin B1-formamidopyrimidine adduct by the opening of the imida- zole ring or can decompose by taminate food items of plant and Introduction depurination and lead to an apurinic animal origin (v Figure 1). site in DNA. Products of the endogenous metabolism of moulds which can be harm- In this contribution, information re- In both cases, DNA replication leads ful to humans and other living or- garding the most relevant mycotox- to gene mutations, whereby afla-

ganisms, are grouped under the ge- ins from a food toxicological point of toxin B1 is a much stronger mutagen

neric term „mycotoxins“. Myco- view, namely aflatoxins, ochratoxin than aflatoxin G1 and aflatoxin M1.

toxins can be formed by outdoor A, Fusarium mycotoxins, ergot alka- In contrast, the aflatoxins B2, G2 und

moulds (e. g. Fusarium spp.), which loids, patulin und citrinin, is sum- M2, which cannot be epoxidized, are

can infest the crops already in the marized. hardly genotoxic. Aflatoxin B1 also field, as well as by indoor moulds exhibits a pronounced cytotoxicity (e. g. Aspergillus spp., Penicillium Aflatoxins which is in part due to the signifi- spp.), which can infest the harvested cant formation of covalent protein crops if they are stored inappropria- Aflatoxins are products of the en- adducts. In this case again it is the

tely (i. e. too high storage humidity, dogenous metabolism of the moulds aflatoxin B1-8,9-epoxide that plays a too long intervals between the har- Aspergillus flavus, Aspergillus para- central role: It is first metabolized to vesting and the drying step or insuf- siticus and Aspergillus oryzae, which the corresponding dihydrodiol and ficient airing). Once they have been pose a great problem in tropical and then to the corresponding dialdehyde released by moulds, they may con- subtropical regions of the world. (v Figure 3). The dialdehyde in turn Consequently, aflatoxins are mainly can easily react with the ε-amino detected in imported products such groups of lysine. as nuts (pistachios, peanuts, hazel- Citation: nuts), dried fruit (figs) and spices Toxicity Steinberg P (2013) A food toxico- (pepper, paprika powder). Aflatoxin

logical contemplation of myco- B1, aflatoxin B2, aflatoxin G1 and In countries, in which the contami-

toxins. Ernaehrungs Umschau in- aflatoxin G2 as well as aflatoxin M1 nation of the food chain with afla- v ternational 60(9): 146–151 and aflatoxin M2 ( Figure 2), which toxins is very high, so-called aflato- This article is available online: are mainly detected in milk and milk xicoses may develop. They are cha- DOI 10.4455/eu.2013.027 products, belong to the group of the racterized by nausea, vomiting, ab- aflatoxins. dominal pain and gastrointestinal

146 Ernaehrungs Umschau international | 9/2013 bleeding, icterus, spasms, coma, Ochratoxin A O O O O pulmonary and cerebral oedema O O Ochratoxins are produced by vari- 9 R R formation as well as necroses and 8 ous Aspergillus and Penicillium fatty degeneration of the liver, kid- O O O O neys and heart. species, among others by Aspergillus H OCH3 H OCH3 ochra ceus, Aspergillus carbonarius AFB1: R = H AFB2: R = H AFM : R = OH AFM : R = OH and Penicillium verrucosum, and 1 2 Because of its extremely strong mu- O O O O tagenicity and cytotoxicity (see chemically represent amide deriva- O O tives of L-phenylalanine (v Figure R R above) aflatoxin B1 is the aflatoxin 4). with the greatest carcinogenic po- O O O OCH O OCH tential and induces liver tumours in The most frequently formed and at H 3 H 3 AFG1: R = H AFG2: R = H experimental animals. The Interna- the same time the most toxic ochra- AFGM1: R = OH AFGM2: R = OH tional Agency for Research on Can- toxin is ochratoxin A. It contami- cer (Lyon, France) which is part of nates grains and grain products, Fig. 2: Structural formulae of the most impor- the World Health Organization legumes, coffee beans, beer, wine, tant aflatoxins in food

(WHO), classified aflatoxin B1 as a raisins, grape juice as well as meat AFB1/2 = aflatoxin B1/2, AFM1/2 = aflatoxin human carcinogen a decade ago [1]. products and is mainly nephrotoxic. M1/2, AFG1/2 = aflatoxin G1/2, AFGM1/2 = aflatoxin GM The chronic exposure of humans to It has been known for a long time 1/2 that because of its structural ho- aflatoxin B1 also leads to the induc- 7 AFB1-N -G tion of liver carcinomas. Moreover, mology to the amino acid L-pheny- - H2N H N dR 2 NH NH it has been known for a number of lalanine ochratoxin A is able to in- N O O O O N O O OH H2O OH O + O years that the risk to develop liver hibit competitively the phenylala- N HN H N 7 H dR dR N O O tumours increases by about a factor nine-tRNA-synthase. However, the H O H O OCH 3 H O OCH above-mentioned enzyme is only 3 of 60 if humans are chronically ex- AFB 1 -FAPY DNA O O posed to aflatoxins through con- inhibited in the presence of very O O O O O 9 H H taminated food and at the same time high concentrations of ochratoxin 8 CYP O O are chronically infected with hepati- A, which in no case are achieved if H O OCH O 3 H OCH3 tis B or C viruses. It has also been humans are exposed to ochratoxin AFB1 AFB1-8,9-epoxide GSH O O pointed out that a relationship be- A-contamined food items. Hence, H2O OH O O GS H O tween the strong contamination of the inhibition of the phenylalanine- OH O O HO H H O the food chain with aflatoxins and tRNA-synthase does not explain the OCH3 O GSH adduct H O OCH the occurrence of the so-called Reye observed renal toxicity. 3 – CO2 AFB1-8,9-diol syndrome (an acute encephalopathy + HC NH3 O O O in combination with a fatty degen- Ochratoxin A induces kidney tu- (H C) O H O 2 3 O Lysin OH O O eration of the liver), most notably in mours in rats. However, the mech- H2C N H HO OCH3 O tropical countries, may exist. anism(s) that lead(s) to the forma- HO OCH3 lysine adduct

Fig. 3: Metabolic activation of aflatoxin B1 to

aflatoxin B1-8,9-epoxide and forma- primary production feed storage tion of covalent adducts with DNA und proteins

AFB1 = aflatoxin B1; AFB1-FAPY = aflato-

xin B1-formamidopyrimidine adduct; outdoor moulds indoor moulds 7 7 AFB1-N -G = aflatoxin B1-N -guanine adduct; CYP = cytochrome P450; dR = de- oxyribose; GSH = glutathione contamination of feed contamination of food of plant O OR1 origin O O O exposure of livestock N O H

CH3 R2 OTA: R1 = H; R2 = CI contamination of food of animal OTB: R1 = H; R2 = H origin 1 2 OTC: R = C2H5; R = CI

Fig. 4: Structural formulae of the most im- Fig. 1: Contamination of food items of plant and animal origin with portant ochratoxins toxins from outdoor and indoor moulds OTA/B/C = ochratoxin A/B/C Ī

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tion of kidney tumours have been other hand, no efficient crop clean- to estrogen receptors in the uterus, controversially discussed up to the up took place in the flour mills. hypothalamus and pituitary gland. present time. Although there were Despite efforts to reduce the amount The affinity of zearalenone to the es- early indications that DNA adducts of ocharoxin A in food items, a cer- trogen receptors α and β is about one are formed in the kidneys of ochra- tain degree of contamination seems tenth to one twentieth of the affinity toxin A-treated rats, it is not clear to be unavoidable at the moment. of the endogenous estrogen 17β- whether these are oxidative DNA le- The tolerable weekly intake amounts estradiol towards the estrogen recep- sions or covalent adducts of DNA to 120 ng/kg body weight. In the tors α and β. In this way zearalenone bases with the mycotoxin or its case of European adult consumers, can lead to marked estrogenic effects. metabolites. the weekly exposure at the moment lies within the range of 15–60 ng In pigs, zearalenone is reduced to α- A kidney disease first described in the ochratoxin A/kg body weight. zearalenol which induces an even 1950s, the so-called „Balkan en- stronger estrogenic response than demic nephropathy“ [2], was linked Fusarium toxins zearalenone itself. The pronounced for a long time to a chronic ochra- reduction of zearalenone to α-zear- toxin A exposure. Symptoms of the Filamentous fungi of the large Fusa- alenol seems to explain why pigs are „Balkan endemic nephropathy“ are: rium genus are able to grow in re- particularly susceptible to zear- – degeneration of the kidney tubuli gions with moderate as well as low alenone-contaminated feed. In this temperatures and are therefore animal species zearalenone leads to – body shrinkage and weight loss widely distributed, also across Eu- swelling of the female genitals and – kidney failure rope. The main toxins produced by to a reduced fertility. In a carcino- – development of kidney and bladder the different Fusarium species are genicity study an increased incidence tumours zearalenone, trichothecenes and fu- of liver and pituitary adenomas in monisins. female mice was observed, whereby Recent studies show that the „Balkan only the number of liver adenomas endemic nephropathy“ is most prob- was significantly enhanced from a Zearalenone ably caused by eating bread that is statistical point of view [5]. In the contaminated with the toxin aristo- Zearalenone contaminates grains past it was hypothesized that zear- cholic acid, which derives from the and grain products, mainly maize alenone was responsible for the mas- birthwort (Aristolochia clematitis) [3, and maize products, but also barley, sive occurrence of premature symp- 4]. On the one hand, the farmers in oat, wheat, sorghum and millet. toms of puberty in very young girls some rural areas of the Balkan could Toxin production can occur in the for example in Puerto Rico and Hun- not afford to buy expensive herbi- field before harvesting as well as gary. However, in these cases one cides, so that weeds could not be dec- during the storage of cereals. Because cannot discard that the girls could imated in the crop fields. On the of its structure, zearalenone can bind have taken up other plant estrogens.

Trichothecenes

16 H 1 10 H Trichothecenes constitute the biggest H3C 9 O 2 group of Fusarium toxins. The most 11 3 1 important compounds in this group 8 6 12 R 7 5 13 are T2 toxin, deoxynivalenol und ni- R5 4 O valenol (v Figure 5). They mainly 4 15 R CH3 R2 contaminate grains (among others 3 14 R oat, wheat and maize) as well as Type A trichothecene R1 R2 R3 R4 R5 grain products, but also potatoes in T-2 toxin OH OAc OAc H OCOCH CH(CH ) 2 3 2 the field or during their storage. HT-2 toxin OH OH OAc H OCOCH2CH(CH3)2 T2 triol OH OH OH H OCOCH2CH(CH3)2 T2 tetraol OH OH OH H OH neosolaniol OH OAc OAc H OH They are strongly cytotoxic and do monoacetoxyscirpenol OH OH OAc H H so by binding to the 60S subunit of diacetoxyscirpenol OH OAc OAc H H ribosomes, thereby inhibiting protein Type B trichothecene R1 R2 R3 R4 R5 nivalenol biosynthesis and inducing apoptosis OH OH OH OH =O deoxynivalenol (DON) OH H OH OH =O in a number of different organs. In 3-acetyl-DON Oac H OH OH =O 15-acetyl-DON animal experiments they particu- OH H Oac OH =O fusarenon-X OH OAc OH OH =O larly led to hemato- and immuno- toxicity, but also to neuro-, embryo- Fig. 5: Structural formulae of important trichothecenes and fetotoxicity (e. g. reduced litter

148 Ernaehrungs Umschau international | 9/2013 size and induction of malformations in rodents). In the case of deoxyni- O COOH valenol, also known as vomitoxin, COOH 2 the most pronounced symptoms of O R OH the intoxication are nausea and 1 vomiting. Due to this, deoxyni- 20 R1 valenol often leads to a reduced feed CH3 O CH3 NH2 intake in pigs and rodents. COOH

If trichothecenes are taken up orally, O COOH a strong mucosal irritation in the 1 2 1 2 FB1: R = OH; R = OH FB3: R = OH; R = H oral cavity and intestine (nausea, 1 2 1 2 FB2: R = H; R = OH FB4: R = H; R = H vomiting, bloody diarrhea) is observed in humans. If they are taken up topically (i.e. through the skin), Fig. 6: Structural formulae of important fumonisins they result in a strong irritation and FB1/2/3/4 = Fumonisin B1/B2/B3/B4 inflammation of the outer skin. During and after the Second World War, a mass disease, which was less folic acid and neural tube defects, However, a prospective study was named alimentary toxic aleukia, was leading to an „open spine“, occur. not able to demonstrate a correlation observed in the former Soviet Union between sphingolipid plasma levels [6]. Symptoms of this disease were: Fumonisins induce a deadly disease as a biomarker of exposure towards in horses, the so-called equine fuminisins and the frequency of oe- – vomiting, abdominal pain, diar- leukoencephalomalacia. In sick ani- sophageal cancer in humans [7]. rhea mals a massive liquefactive necrosis Furthermore, in the past an increased – leucopenia of the subcortical white matter of incidence of neural tube defects in – bone marrow aplasia one or both cerebral hemispheres, ac- babies at the border between Mexiko – high susceptibility to infections companied by oedema formation in and the USA, in China and in South – fever the immediate surroundings of the Africa, regions in which maize was – bleeding from the nose, throat and necrotic areas, is observed. In 1989, highly contaminated with fumon- gums as a consequence of necroses thousands of pigs died in the USA isins, was observed. in the oral cavity and oesophagus after feeding them with maize that The consumption of mouldy, win- was highly contaminated with fu- Ergot alkaloids tered grains contaminated with tri- monisins, whereby the cause of chothecenes (mainly T2 toxin) was death was pulmonary oedema. In The fungus Claviceps purpurea, assumed to be the cause of the rats and mice, fumonisins induce known as „ergot“, grows parasiti- above-mentioned disease. liver and kidney tumours. cally on cereal plants, mainly rye, in humid years. Up to the present time, Epidemiologic studies in South more than 30 ergot alkaloids have Fumonisins Africa, the People’s Republic of been identified, all of which are ly- Fumonisins (v Figure 6), which al- China, Iran, Kenya, Brazil and the sergic acid or clavine derivatives most exclusively contaminate maize, USA suggest that there might be a (v Overview 1). interfere with the biosynthesis of correlation between the contamina- sphingolipids. These molecules are tion of food with fumonisins and the Symptoms of an acute intoxication needed in all eukaryotic cells to build incidence of oesophageal cancer. with ergot alkaloids are sensation of up cell structures and to regulate a number of different cell functions. Due to a fumonisin-induced inhibition of ceramide synthase (sphinga- Lysergic acid amide alkaloids ergine, ergometrine nine N-acyl transferase), free sphin- Lysergic acid peptide alkaloids ergotamine group (e. g. ergotamine, ergosine, ganine accumulates in the liver and ergosecaline) kidneys of rodents and thereafter ergotoxine group (e. g. α- and β-ergocryptine, damages these organs. Because of the ergocornine, ergocristine) missing sphingolipids, the folic acid ergoxine group (e. g. ergostine) transporter, among other trans- Clavine alkaloids agroclavine, chanoclavine porters, is impaired in mice, so that the placenta and the embryo take up Overview 1: Ergot alkaloids Ī

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thirst, abdominal pain, nausea, due to the consumption of rye – gangrenous ergotism (burning headache, paraesthesias, seizures bread made from ergot-infected pain, vascular spasms, loss of and death due to respiratory para- grain occurred in Europe since the limbs and death) th lysis or circulatory collapse. Uterine 9 century. In this regard, two – convulsive ergotism (headache, bleeding and abortions have often forms of the chronic intoxication nausea, seizures, painful muscle been described. Mass intoxications were described: contractions and psychoses)

The complex effects of ergot are Food Mycotoxin Number Percentage of Mean mainly due to its high content of ly- of samples with [μg/kg sergic acid derivatives, which show samples quantifiable type of structural similarities to the neuro- levels [%] product] transmitters noradrenaline, dopa- v buckwheat grains aflatoxin B1 12 16.7 1.78 mine and serotonin ( Figure 7). The vasoconstrictory effect of ergota- buckwheat grains sum of aflatoxine 12 16.7 2.14 mine is used in human medicine to B1, B2, G1 and G2 treat acute migraine attacks as well peanut (roasted, aflatoxin B 133 2.3 0.126 1 as postpartum to decrease uterine with shell) bleeding. peanut (roasted, sum of aflatoxine 133 2.3 0.200 with shell) B , B , G und G 1 2 1 2 The contamination of grains with pumpkin seed aflatoxin B1 117 1.7 0.006 ergot is a problem at the present pumpkin seed sum of aflatoxine 117 2.6 0.017 time, whereby the degree of contam-

B1, B2, G1 und G2 ination varies from year to year. Again and again flours with clearly almond (with aflatoxin B1 99 5.1 0.116 shell, unroasted) higher ergot contents than the allowed 0.05 %, which correspond to almond (with sum of aflatoxine 99 6.1 0.126 about 1 mg total ergot alkaloids/kg shell, unroasted) B1, B2, G1 und G2 grain, appear on the market. Preg- pepper (black, aflatoxin B 109 25.7 0.158 1 nant women, unborn children and ground) breast-fed babies are the groups at pepper (black, sum of aflatoxine 109 27.5 0.180 risk. Precautionary consumer pro- ground) B , B , G und G 1 2 1 2 tection demands that only grains, sesame aflatoxin B1 102 18.4 0.076 which are to the greatest possible ex- sesame sum of aflatoxine 102 28.2 0.130 tent ergot-free, should be industri-

B1, B2, G1 und G2 ally processed or directly reach the buckwheat grains ochratoxin A 102 49.0 0.560 consumers. peanut (roasted, ochratoxin A 123 48.8 1.44 with shell) Patulin

pumpkin seed ochratoxin A 111 14.4 0.066 Patulin is produced by Aspergillus almond (with shell, ochratoxin A 93 6.5 0.057 clavatus, Aspergillus giganteus, Peni- unroasted) cillium patulinum, Penicillium expan- pepper (black, ochratoxin A 106 61.3 1.33 sum and Penicillium urticae. In the ground) past, it was mainly detected in apple sesame ochratoxin A 99 10.9 0.078 juices, but also in flour products and meat. It possesses a high affinity to pils ochratoxin A 93 60.2 0.018 thiol groups and can therefore in- wheat flour ochratoxin A 118 30.5 0.123 hibit for example membrane-bound rye flour Summe T2-Toxin 64 4.7 0.213 ATPases. Following its oral uptake, und HT2-Toxin mucosal irritations in the intestinal soy bean sum of T2-toxin 48 0 tract together with nausea, vomit- and HT2-toxin ing and diarrhea are observed. Al- though patulin is associated with a wheat flour sum of T2-toxin 62 0 and HT2-toxin very low health risk when compared to aflatoxins, no mouldy apples Tab. 1: Aflatoxin, ochratoxin A, T2 toxin and HT2 toxin contents in foods should be used to produce apple according to Food Monitoring 2011 [8] juices.

150 Ernaehrungs Umschau international | 9/2013 International Agency for Research on Cancer (IARC). (Hg). Monographs on the Evaluation O R of Carcinogenic Risks to Humans. 82. Aufl., C OH O N CH3 N NH NH NH H3C IARC Press, Lyon (2002), S. 171–293 H H H R = NH N O HO 2. Stefanovic V, Radovanovic Z (2008) Balkan O CH2 HO endemic nephropathy and associated urothe-

N N O O lial cancer. Nat Clin Pract Urol 5: 105–112 H H H H OH OH 3. Grollman AP, Shibutani S, Moriya M et al. lysergic acid ergotamine serotonin noradrenaline dopamine (2007) Aristolochic acid and the etiology of endemic (Balkan) nephropathy. Proc Natl Acad Sci USA 104: 12129–12134 Fig. 7: Structural formula of lysergic acid and ergotamine and structural 4. Jelakovi B, Karanovi S, Vukovi -Lela I et al. relationship with serotonin, noradrenaline and dopamine (2012) Aristolactam-DNA adducts are a biomarker of environmental exposure to aristolochic acid. Kidney Int 81: 559–567 Citrinin three buckwheat grain samples from 5. National Toxicology Program (1982) Carcino- Germany and one from the People’s genicity bioassay of zearalenone in F344/N Citrinin is formed by various differ- Republic of China, the determined rats and B6C3F1 mice. Natl Toxicol Program ent Penicillium, Aspergillus and contents exceeded the maximum al- Tech Rep Ser 235: 1–155 Monascus species and is present in red lowed levels of 3 µg/kg food. The 6. Joffe AZ. Fusarium poae and F. sporotri- yeast rice, a rice variety that is fer- Fusarium toxins T2 and HT2 were chioides as principal causal agents of alimen- mented by Monascus spp. In South- detected in 4.7 % of the rye flour tary toxic aleukia. In: Wyllie TD, Moorhouse east Asia, red yeast rice is tradition- samples analyzed. In contrast, no LG (Hg). Mycotoxic fungi, mycotoxins, myco- ally used as a natural food additive T2-toxin and HT2-toxin were de- toxicosis: an encyclopedia handbook. 3. Aufl., and in the USA it was marketed as a tected in the soy bean and wheat Marcel Dekker, New York (1978), S. 21–86 food additive with a cholesterol-low- flour samples analyzed in 2011. 7. Shephard GS, van der Westhuizen L, Sewram ering effect until 2000. Citrinin itself V (2007) Biomarkers of exposure to fumonisin chronically damages the epithelial In summary, the number of cases, in mycotoxins: A review. Food Addit Contam 24: cells of the kidney tubuli, may in- which the maximum allowed myco- 1196–1201 duce kidney tumours and is muta- toxin levels were exceeded, was very 8. Bundesamt für Verbraucherschutz und Lebens- genic, aneuploidogenic and terato- low in 2011. However, as very re- mittelsicherheit (2011) Berichte zur Lebens- genic. cently demonstrated by the detection mittelsicherheit 2011. URL: www.bvl.bund.

of aflatoxin B1 in forage maize from de/SharedDocs/Downloads/01_ Lebensmit Contamination of foods Serbia [9], the mycotoxin monitor- tel/01_lm_mon_dokumente/01_Monitor with aflatoxins, ochratoxin ing of foods and animal feed is still of ing_Berichte/lmm_bericht_2011.pdf?_blob= great relevance. publicationFile&v=4 Zugriff 12.08.13 A and Fusarium toxins 9. Niedersächsisches Ministerium für Ernährung, The content of aflatoxins, ochratoxin Landwirtschaft und Verbraucherschutz

A and the Fusarium toxins T2 and (2013) Aflatoxin B1 in Futtermais - Aktueller HT2 were determined in a variety of Prof. Dr. Pablo Steinberg Sachstand. URL: www.ml.niedersachsen.de/ food items in the context of the Re- Institute for Food Toxicology and Analytical portal/live.php?navigation_id=27751&arti Chemistry cle_id=113258&_psmand=7 Zugriff 12. port on Food Monitoring 2011 in University of Veterinary Medicine Hannover v Germany [8] ( Table 1). Bischofsholer Damm 15, 30173 Hannover, 08.13 Germany The highest amounts of aflatoxins E-Mail: [email protected] were detected in buckwheat grains, Conflict of Interest whereby an exceedance of the al- The author declares no conflict of interest ac- lowed maximum aflatoxin levels cording to the guidelines of the International only occurred in one peanut sample Committee of Medical Journal Editors. from Taiwan and one buckwheat grain sample from Germany. The highest mean ochratoxin A contents among all food items analyzed were References detected in peanuts. Moreover, markedly higher levels of ochratoxin 1. International Agency for Research on Cancer A were measured in part in buck- (IARC). Some traditional herbal medicines, DOI: 10.4455/eu.2013.027 wheat grains than in wheat flour; in some mycotoxins, naphthalene and styrene. In:

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