Mycotoxins and Human Health

chapter 6. Mycotoxins and human health Summary especially in vulnerable populations. 1. Introduction For fumonisins, studies indicate a Mycotoxins have been investigated possible role in oesophageal cancer This chapter covers the effects on in relation to a wide range of adverse and in neural tube defects, although human health of the major mycotoxins human health effects, but the evidence no definitive conclusions can be occurring in foods. This chapter also for all but a small number of associations drawn at present. For deoxynivalenol includes information on mechanisms is limited. Thus, the full impact on human and other trichothecenes, exposure of action of mycotoxins in humans CHAPTER 6 CHAPTER health of the widespread exposure has been linked to acute poisoning where relevant to the adverse health to mycotoxins remains to be defined. outbreaks in large numbers of effects under consideration. No The main exception is for aflatoxins; subjects. For ochratoxin A and attempt is made at a comprehensive epidemiological, experimental, and zearalenone, the human health review, but at appropriate points we mechanistic studies have contributed effects remain undefined. The limited refer to more extensive accounts. to establishing aflatoxins as a tools available to accurately assess The major source of human cause of human liver cancer, with a human exposure to mycotoxins and exposure to mycotoxins is consump- particularly elevated risk in people the relative paucity of epidemiological tion of contaminated foods. Exposure chronically infected with hepatitis B studies need to be addressed if the full is highest when those foods are dietary virus. In addition, acute aflatoxicosis extent of the adverse effects of these staples, such as maize, groundnuts, or after exposure to high dietary toxin common dietary contaminants is to be various other cereals. Exposures to levels has been demonstrated. The understood and adequate public health metabolites or parent toxins may also impairment of child growth by aflatoxin measures taken. In this respect, newly occur by consumption of contaminated exposure early in life remains an established biomarkers of exposure at milk and milk products. We covered important subject of study. More the individual level are proving valuable the dietary sources of mycotoxin information is also required on the in improving exposure assessment in exposure in some detail in Chapter 1. potential immune effects of aflatoxins, epidemiological studies. In this chapter, we also consider Chapter 6. Mycotoxins and human health 87 occupational exposures in granaries 2. Aflatoxins but is less mutagenic than AFB1, and other food and feed processing reflecting the stearic chemistry of the due to mycotoxins contained in dusts Aflatoxins are produced in a wide respective epoxides; the AFB1-8,9- from contaminated grains. The specific range of commodities by Aspergillus epoxide intercalates more readily into effects due to particular mycotoxins are flavus and A. parasiticus, and the DNA double helix than does the discussed in Sections 2–6. Additional, occasionally other Aspergillus species. equivalent AFG1 molecule, resulting in more general information on health The commodities most at risk are higher levels of DNA adduct formation problems associated with mycotoxins maize and groundnuts in tropical areas for a given dose. Minimal information in grain dusts is covered in Section 7. (see Chapter 1). exists about the importance of The human health effects the reactive epoxide for the non- considered here encompass acute 2.1 Mechanisms mutagenic actions of aflatoxins or poisoning, cancer, other chronic indeed about the biological effects of diseases, and biological effects, Until recently, attention on af- aflatoxins independent of metabolic including growth impairment and latoxins has been focused on activation to the 8,9-epoxide. Unlike immunomodulation. their carcinogenic effects. For AFM2, AFM1 contains an 8,9 double One of the major limitations more detailed information, see the bond and hence can be bioactivated in assessing the effects of extensive reviews in IARC (2002), to the reactive 8,9-epoxide. mycotoxins on health has been WHO (2002), and Wild and Gong A significant observation in the inability to accurately assess (2010). Consideration is usually given terms of aflatoxin carcinogenicity is exposure at the individual level. to the naturally occurring aflatoxins the association between exposure The development of validated in the diet – aflatoxins B1 (AFB1), B2 and a specific mutation in the TP53 biomarkers for aflatoxins has greatly (AFB2), G1 (AFG1), and G2 (AFG2) – tumour suppressor gene in liver assisted epidemiological studies and or to AFB1 alone, or more rarely to cancer (hepatocellular carcinoma allowed an evaluation of aflatoxins aflatoxins M1 (AFM1) and M2 (AFM2), [HCC]). In HCC tumours from patients in relation to cancer, aflatoxicosis, the hydroxylation products of AFB1 who are from regions endemic for child growth impairment, and immune and AFB2, respectively, that occur aflatoxin and who are chronically effects (see Wild and Gong, 2010). in milk. This distinction between the infected with hepatitis B virus (HBV), Development of validated biomarkers type of aflatoxin exposures under a high prevalence exists of a specific for fumonisins (Wild and Gong, 2010; consideration is important but is missense mutation in the gene, Van der Westhuizen et al., 2011) rarely considered, particularly when namely an AGG → AGT (Arg → Ser) and deoxynivalenol (Meky et al., studying adverse health effects other point mutation at codon 249 (codon 2003; Turner et al., 2008a, 2008b, than cancer. 249ser) (IARC, 2002; Hussain et al., 2008c) also offers promise for future Given the focus on mutagenicity 2007). This mutation is extremely rare studies of the human health effects and carcinogenicity, most studies in HCC associated with HBV in areas of these mycotoxins. However, have been of AFB1, which, due to the where aflatoxins are uncommon, the biomarker field for mycotoxins presence of a double bond at the 8,9 but it is as yet unclear whether HBV also offers a cautionary tale: an position, can be metabolized to the infection influences occurrence of unvalidated biomarker for ochratoxin reactive AFB1-8,9-epoxide, which the mutation in HCC from aflatoxin- A in plasma or serum has been binds to cellular macromolecules endemic areas. used to assess dietary exposure including DNA (for more detail, see The major human cytochrome to this toxin, but subsequent Wild and Turner, 2002). The major P450 (CYP) enzymes involved in careful duplicate diet studies have DNA adduct is AFB1-N7-guanine, and aflatoxin metabolism are CYP3A4, shown that this biomarker does not this pro-mutagenic lesion commonly 3A5, and 1A2, and the predominant reflect intake at the individual level results in a G → T transversion site of bioactivation is the liver, (Gilbert et al., 2001). Nevertheless, mutation. AFB1-N7-guanine can although CYP3A4 expression in the availability of biomarkers to also be detected in the urine and the human intestine means that measure exposure to mycotoxins used as an exposure biomarker in metabolism may also occur in that provides new opportunities for more epidemiological studies. AFB2 and organ (Wild and Turner, 2002; systematic monitoring of exposure AFG2 are generally considered to be Kamdem et al., 2006; Thelen and in populations as well as improved far less biologically active due to the Dressman, 2009). The contribution of etiological studies. absence of the 8,9 double bond. AFG1 these enzymes to AFB1 metabolism in can be bioactivated to the 8,9-epoxide exposed people will depend on both 88 the affinity and level of expression An understanding of the Baumgartner et al., 2005; Lewis et of the different enzymes; CYP3A4 metabolism, DNA damage, and al., 2005). These outbreaks resulted appears to be the most important in induction of mutations in people in several hundred deaths associated generating the exo-8,9-epoxide, and exposed to aflatoxins in the diet with consumption of maize heavily the relative contribution of CYP3A5, has contributed to the overall contaminated with aflatoxin. A case– which also produces the exo-8,9- assessment of their adverse health control study of aflatoxicosis, defined epoxide, varies by individual (Kamdem effects (Groopman et al., 2008; Wild as acute jaundice of unknown origin, et al., 2006). In fact, CYP3A5 and Gong, 2010). The major health found that aflatoxin levels in foods expression is polymorphic and effects linked to aflatoxin exposure from affected households were varies by ethnic group; for example, are described briefly here. much higher than those in foods 40% of African Americans show no from unaffected households. Similar expression due to identified genetic 2.2 Aflatoxicosis differences between cases and polymorphisms. Such polymorphisms controls were found when aflatoxin may affect sensitivity to the toxic Sporadic historical accounts of biomarker levels in blood were effects of aflatoxins (Wojnowski et al., human poisoning with aflatoxins examined (Azziz-Baumgartner et al., 2004). CYP1A2 leads predominantly were reported, but these early 2005; McCoy et al., 2008). to formation of the hydroxylated AFM1 studies were not definitive in The association of aflatoxin metabolite and the AFB1-endo-8,9- assigning causation (Hall and Wild, contamination of maize with acute epoxide, which does not form DNA 1994). In 1974, hepatitis cases due hepatitis and aflatoxicosis is well adducts. to

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