Natural occurrence of mycotoxins in medicinal plants: a review.

Fungal Genetics and Biology xxx (2014) xxx–xxx

Contents lists available at ScienceDirect

Fungal Genetics and Biology journal homepage: www.elsevier.com/locate/yfgbi

Review

Natural occurrence of mycotoxins in medicinal plants: A review Samina Ashiq a,⇑, Mubbashir Hussain b, Bashir Ahmad a a b

Centre of Biotechnology & Microbiology, University of Peshawar, Pakistan Department of Microbiology, Kohat University of Science and Technology, 26000, Pakistan

a r t i c l e

i n f o

Article history: Received 25 July 2013 Accepted 24 February 2014 Available online xxxx Keywords: Mycotoxins Medicinal plants Herbs Aflatoxins Ochratoxin A Contamination

a b s t r a c t Medicinal plants are widely used as home remedies and raw materials for the pharmaceutical industries. Herbal remedies are used in the prevention, treatment and cure of disorders and diseases since ancient times. However, use of medicinal herbs may not meet the requirements of quality, safety and efficacy. During harvesting, handling, storage and distribution, medicinal plants are subjected to contamination by various fungi, which may be responsible for spoilage and production of mycotoxins. The increasing consumption of medicinal plants has made their use a public health problem due to the lack of effective surveillance of the use, efficacy, toxicity and quality of these natural products. The increase in use of medicinal plants may lead to an increase in the intake of mycotoxins therefore contamination of medicinal plants with mycotoxins can contribute to adverse human health problems and therefore represents a special hazard. Numerous natural occurrences of mycotoxins in medicinal plants and traditional herbal medicines have been reported from various countries including Spain, China, Germany, India, Turkey and from Middle East as well. This review discusses the important mycotoxins and their natural occurrences in medicinal plants and their products. Ó 2014 Elsevier Inc. All rights reserved.

Contents 1. 2. 3.

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6.

7.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mycotoxins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Aflatoxins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Environmental factors affecting aflatoxin production. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Medical implications of aflatoxins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Permissible limits of aflatoxins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ochratoxin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Environmental factors affecting OTA production . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Medical implications of ochratoxin A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Permissible limits of ochratoxin A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Fumonisins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Medical implications of fumonisins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Permissible limits of fumonisins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Zearalenone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1. Medical implications of zearalenone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2. Permissible limits of zearalenone. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Deoxynivalenol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.1. Medical implications of deoxynivalenol. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2. Permissible limits of deoxynivalenol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abbreviations: AF, aflatoxin; OTA, ochratoxin A; FB, fumonisins; ZEA, zearalenone; DON, deoxynivalenol.

⇑ Corresponding author. Address: Centre of Biotechnology & Microbiology, University of Peshawar, Peshawar 25120, Pakistan. E-mail addresses: [email protected] (S. Ashiq), [email protected] (M. Hussain), [email protected] (B. Ahmad). http://dx.doi.org/10.1016/j.fgb.2014.02.005 1087-1845/Ó 2014 Elsevier Inc. All rights reserved.

Please cite this article in press as: Ashiq, S., et al. Natural occurrence of mycotoxins in medicinal plants: A review. Fungal Genet. Biol. (2014), http:// dx.doi.org/10.1016/j.fgb.2014.02.005

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S. Ashiq et al. / Fungal Genetics and Biology xxx (2014) xxx–xxx

8.

Mycotoxin contamination in medicinal plants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.1. Aflatoxin contamination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.2. Ochratoxin contamination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.3. Fumonisin contamination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.4. Zearalenone and Deoxynivalenol contamination. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.5. Multi-mycotoxin contamination. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9. Risk assessment studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10. Inhibitory effects of medicinal plants on mycotoxins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11. Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Fungi are a large group of diverse eukaryotic organisms which include yeasts and moulds. Moulds (filamentous fungi) are widely distributed in nature. Due to their versatile nutritional requirements, they are common contaminants and under favorable conditions of humidity and temperature, propagate on different commodities and beverages and produce mycotoxins (Brera et al., 1998). Medicinal plants are frequently contaminated with toxigenic fungi originating in the soil. Numerous natural occurrences of mycotoxins in medicinal plants and traditional herbal medicines have been reported from various countries. Data from India suggest that higher levels of mycotoxins are present in locally available medicinal plants. Studies from Turkey reveal that dried figs are highly contaminated with aflatoxins, ochratoxin A and fumonisin B1. One area of concern is high levels of ochratoxin A contamination in licorice roots and products. Traditional Chinese medicines are also reported to contain exceeding levels of aflatoxins and ochratoxin A. 2. Mycotoxins Mycotoxins are toxic secondary metabolites produced by moulds such as Aspergillus, Penicillium, Fusarium and Alternaria (Zain, 2011). Mycotoxins can be defined as ‘‘fungal metabolites that when ingested, inhaled or absorbed through the skin cause illness or human and animal death’’ (Pitt, 1996). Mycotoxins cause variety of toxic effects. They are carcinogenic, neurotoxic, teratogenic and immunotoxic (FAO, 2001; Petzinger and Ziegler, 2000). Currently 400 different mycotoxins have been recognized (Zinedine and Mañes, 2009). The most important mycotoxins from human and domestic animal health point of view are aflatoxins ochratoxin A, fumonisins, zearalenone and deoxynivalenol (Miller, 1995; Santos et al., 2009). These are commonly present as contaminants in different commodities including cereals, nuts, herbal teas and spices. Crops that are stored for more than a few days become susceptible to mould growth and mycotoxin production. Contamination can occur pre-harvest or post-harvest stage (EMAN, 2003). Tropical climate and poor storage are the suitable environmental conditions that support mould growth and mycotoxin production. Mycotoxin production can be enhanced by ecological conditions like drought or damage by insects or mechanical harvesting during cultivation and storage (Tassaneeyakul et al., 2004).

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while all four isoforms (B1, B2, G1, G2) are produced by Aspergillus parasiticus (Bennett and Klich, 2003). Aflatoxin B1 is the most toxic of the aflatoxins and most potent naturally occurring hepatocarcinogen (IARC, 1993; Squire, 1989). 3.1. Environmental factors affecting aflatoxin production Aflatoxin production is affected by several factors. Major factors are the fungal strain, substrate potential, moisture content, temperature and relative humidity. The minor factors that affect aflatoxin production include inoculum’s potential, crop variety, oxygen supply, insect interaction and storage conditions (Bhatnagar et al., 2003). Warm and moist conditions of tropical and subtropical countries are favorable for aflatoxin production and it is enhanced by poor crop storage (Busby and Wogan, 1984). 3.2. Medical implications of aflatoxins Aflatoxins are amongst the most powerful mutagens and carcinogens known (FAO, 1997). The International Agency of Research on Cancer (IARC) has classified AFs as Group 1 human carcinogen (IARC, 1993). Aflatoxins and hepatitis B virus (HBV) infection synergistically develop approximately thirty-fold higher hepatocellular carcinoma risk in aflatoxin-exposed, HBV-positive individuals, as compared to HBV-negative persons (Groopman and Kensler, 1996). Other toxic effects of aflatoxins include genotoxicity, teratogenicity and immunosuppressive activity. Aflatoxin B1 LD50 values for most animal species ranges from 1 to 50 mg/kg body weight (Leeson et al., 1995). 3.3. Permissible limits of aflatoxins The aflatoxin contamination of foodstuff and animal feed is controlled by legal limits. Worldwide accepted range of the total aflatoxin in foodstuffs is 1–20 ppb and in the feed the permissible limit range is 0–50 ppb. The limits for the aflatoxin M1 in the milk for human consumption are 0.05–0.5 ppb (FAO, 2003). Maximum limits of 2 lg/kg for AFB1 and 4 lg/kg for total aflatoxins in herbal drugs have been set by the European Pharmacopoeia (EP, 2011). However due to the fact that most herbs are processed before consumption, Liu et al. (2012) proposed higher maximum limits of 5 lg/kg and 10 lg/kg for AFB1 and total aflatoxins respectively.

3. Aflatoxins 4. Ochratoxin Aflatoxins (AFs) are a class of mycotoxins produced mainly by toxigenic strains of Aspergillus flavus and Aspergillus parasiticus and rarely by Aspergillus nomius which can grow on various kinds of foods, beverages and medicinal plants. Aflatoxins are the most important human mycotoxins (WHO, 1998) and are among the most toxic mycotoxins (Passone et al., 2010; Sardiñas et al., 2011). There are nearly 20 different types of aflatoxins of which the four major ones are aflatoxins B1, B2, G1 and G2. Aflatoxin B1 (AFB1) and aflatoxin B2 (AFB2) are produced by Aspergillus flavus,

Ochratoxins are another family of mycotoxins produced by many species of Aspergillus and Penicillium. The family of ochratoxins consists of three members, A, B, and C. Ochratoxin A (OTA) is the most abundant and the most toxic of the three while ochratoxin B (OTB) and ochratoxin C (OTC) are less important and less common (Li et al., 1997; Van der Merwe et al., 1965). OTA is mainly produced by Penicillium verrucosum, P. nordicum, Aspergillus niger, A. ochraceus and A. carbonarius under diverse environmental



conditions (Abarca et al., 2001; Cabañes et al., 2010). OTA is found as a common contaminant of wide variety of cereals, vegetables, dried fruits, spices, coffee, fermented beverages and medicinal plants (Janati et al., 2012; Magnoli et al., 2006; Yang et al., 2010). 4.1. Environmental factors affecting OTA production Production of OTA is affected by various factors including temperature, moisture, incubation time, light and medium composition. Ochratoxin A production in Aspergilli species is the effect of the interaction of many factors like fungal strain, composition of the substrate and environmental factors such as temperature, oxygen, carbon dioxide, humidity, pH and incubation period. The amount of OTA produced by different fungal species is strongly influenced by temperature and humidity (Sanchis and Magan, 2004). 4.2. Medical implications of ochratoxin A Ochratoxin A exerts several toxic effects. It is nephrotoxic, teratogenic, genotoxic, neurotoxic, hepatotoxic and has immunosuppressive properties (Pfohl-Leszkowicz and Manderville, 2007). It has been classified as a possible Group 2B human carcinogen (IARC, 1993). OTA is also associated with a fatal human kidney disease called Balkan Endemic Nephropathy (Bennett and Klich, 2003; Pena et al., 2006). The LD50 values range from 0.2 to 58.3 mg/kg among the assayed animals (Pfohl-Leszkowicz and Manderville, 2007). 4.3. Permissible limits of ochratoxin A According to the European Union Commission Regulation (EC, 2006), maximum allowable concentrations for OTA in raw cereals and products derived from cereals are 5 lg/kg and 3 lg/kg respectively. Moreover maximum range of 0.5–10 lg/kg are set in some food items (cereal-based weaning foods, baby foods etc.).

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6. Zearalenone Zearalenone (ZEA) is a non-steroidal estrogenic mycotoxin which is produced by Fusarium species mainly F. graminearum and F. culmorum (Kuiper-Goodman et al., 1987; Logrieco et al., 2002). ZEA contamination has been reported worldwide in many cereal crops including wheat, maize, barley, sorghum and oats (Hewitt et al., 2012; Tanaka et al., 1988). It is a heat-stable compound and it does not degrade during processing or cooking of food (El-Hoshy, 1999). 6.1. Medical implications of zearalenone Following oral administration, zearalenone is rapidly absorbed and metabolized into a-zearalenol and b-zearalenol. Competitive binding of ZEA and its metabolites to estrogen receptors in in vitro systems have been reported (Eriksen and Alexander, 1998). Studies on various animal species (guinea-pigs, rat, mice, rabbits, hamsters) revealed that ZEA causes alterations in the reproductive tract which may result in severe reproductive disorders, infertility and change in serum levels of progesterone (Gaumy et al., 2001; JECFA, 2000; Yang et al., 2007). ZEA is also associated with early pubertal changes in young children (Saenz de Rodriguez et al., 1985; Schoental, 1983; Szuets et al., 1997). The carcinogenicity of ZEA was evaluated by International Agency for Research on Cancer and it was found to be possibly carcinogenic to human (IARC, 1993). ZEA has been reported to be associated with esophageal cancer (Gao and Yoshizawa, 1997), human cervical cancer and endometric hyperplasia (Tomaszewski et al., 1998). 6.2. Permissible limits of zearalenone For ZEA, several countries have set a maximum limit ranging from 20 to 1000 lg/kg in raw and processed food items (EC, 2006; FAO, 2004). A maximum limit of 60 lg/kg in corn and wheat is set by the Ministry of Health of the People’s Republic of China (2005).

5. Fumonisins 7. Deoxynivalenol Fumonisins (FB) are mycotoxins that are produced by many species of Fusarium including Fusarium proliferatum and F. verticillioides. Fumonisins are worldwide reported as contaminants of corn and corn products (Scaff and Scussel, 2004). Fumonisins are fairly stable compounds and processing such as heat treatment under alkaline conditions, only removes the tricarballyic acid residues leaving a molecule which is still toxic (Hopmans and Murphy, 1993). Fumonisin B1 (FB1), a fumonisin derivative, is the most toxic and common one, found in beer (Torres et al., 2001), asparagus (Liu et al., 2005), figs (Karbancıoglu-Guler and Heperkan, 2009), medicinal plants (Omurtag and Yazicioglu, 2004) and black tea (Martins et al., 2001). Other derivates, FB2 and FB3, occur in lower concentration levels (Rheeder et al., 2002).

The mycotoxin deoxynivalenol (DON) also known as vomitoxin is a type-B trichothecene. It is mainly produced by Fusarium culmorum and F. graminearum which grow on various kinds of grains such as oats, barley and wheat (Richard, 2007; Sinha and Savard, 1996). 7.1. Medical implications of deoxynivalenol At high concentrations DON induces vomiting and at extremely higher levels DON is fatal (Forsell et al., 1987; Rotter et al., 1996). DON inhibits DNA and protein synthesis and also causes immunosuppression. It is also known to alter brain neurochemicals (Coppock et al., 1985).

5.1. Medical implications of fumonisins

7.2. Permissible limits of deoxynivalenol

Fumonisins are found to be associated with human esophageal cancer (Myburg et al., 2002; Rheeder et al., 1992). FB1 has been classified as ‘possibly carcinogenic to humans’ in Group 2B (IARC, 1993). Other toxic effects of FB1 in various animal species include hepatotoxicity, nephrotoxicity and immunosuppressive activity (EHC, 2000).

European commission (EC, 2006) has set maximum limits of 200 lg/kg for processed cereal based food and 1250 lg/kg for unprocessed cereals.

5.2. Permissible limits of fumonisins Fumonisins (FB1 + FB2) levels in maize and maize-based foods for direct human consumption are regulated with a maximum level of 1000 lg/kg (EC, 2007).

8. Mycotoxin contamination in medicinal plants According to WHO, ‘‘a medicinal plant is any plant which, in one or more of its organs, contains substances that can be used for therapeutic purposes, or which are precursors for chemo-pharmaceutical semi-synthesis’’ (WHO, 1977). A plant, when designated as ‘‘medicinal’’, it is meant that the said plant is useful as a therapeutic agent or drug or an active ingredient of a medicinal formulation.


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Medicinal plants may thus be defined as ‘‘a group of plants that exhibit some special properties that qualify them as articles of drugs and therapeutic agents, and are used for medicinal purposes’’ (Ghani, 1998). Medicinal plants have been used in the treatment, prevention and cure of disorders and diseases and also to promote health since ancient times. Worldwide medicinal herbs are consumed as home remedies and raw materials for the pharmaceutical industries (Astin, 1998). According to an estimate about 25–50% of the pharmaceutical drugs are derived from different plant materials (Cowan, 1999). An estimated 80% of the world’s population use herbal medicines for some aspects of primary health care (Chan, 2003) and about 89% population of developing countries use traditional herbal medicines (Shaw, 1998). Nowadays, the consumption of medicinal herbs is increasing; however, use of medicinal herbs may not meet the requirements of quality, safety and efficacy. The increasing consumption of medicinal plants has made their use a public health problem due to the lack of effective surveillance of the use, efficacy, toxicity and quality of these natural products. Medicinal plants are frequently contaminated with toxigenic fungi originating in the soil. During harvesting, handling, storage and distribution, these plants are subjected to contamination by various fungi, which may be responsible for spoilage and production of mycotoxins (Calixto, 2000; Rizzo et al., 2004). The condition is serious especially in developing countries, where there are poor production practices [i.e., good agricultural practices (GAP) and good harvesting practices (GHP) are inadequate]. Moreover the poor conditions of storage and transportation contribute to fungal contamination and increase the risk of mycotoxin production (Iqbal et al., 2011). The increase in use of medicinal plants may lead to an increase in the intake of mycotoxins therefore contamination of medicinal plants with mycotoxins can contribute to adverse human health problems and therefore represents a special hazard. Mycotoxin occurrence in plant-derived foods, feeds and other commodities causes considerable losses related to human health, livestock and poultry productivity (Hussein and Brasel, 2001). Worldwide, as much as 25% of crops are affected by mycotoxins yearly which is also associated with substantial economical losses (FAO, 2001). Although maximum safe levels for aflatoxins, OTA, fumonisins, ZEA and DON in a variety of foodstuffs have been regulated by European Union (EU), but in case of medicinal plants, official regulation for only AF and OTA are established for some herbs (Table 1). In contrast to AF and OTA, permissible limits for fumonisins, ZEA and DON in medicinal herbs are not regulated by the European Union. There is no official legislation for all mycotoxins contamination of medicinal herbs. The presence of mycotoxins in several medicinal plants has been reported: 8.1. Aflatoxin contamination Aflatoxin contamination in medicinal plants has been reported from various countries. In Egypt, 29% of the 31 samples of herbs

and medicinal plants were determined to contain AFB1 with a mean concentration of 49 ppb (Selim et al., 1996). However samples of peppermint, chamomile flowers, tilio, anise and caraway from Egyptian market were found free of aflatoxins while the predominant fungal species isolated from the samples were Aspergillus niger, Fusarium and Penicillium species (Abou-Arab et al., 1999). Similarly in another study in Egypt, different samples of medicinal plants, showing presence of moulds (Aspergillus, Penicillium, Fusarium etc.), were tested to be free of aflatoxins (Abou Donia, 2008). Higher levels of aflatoxins were detected in medicinal plants in India. 14 out of 15 samples (Roy et al., 1988) and 30 out of 37 samples (Roy and Chourasia, 1989) of medicinal plants from local Indian storehouses were found contaminated with aflatoxins. In another study, AFB1 and citrinin were detected in medicinal plants at levels ranging from 0.02 to 1.18 lg/g and 0.01 to 0.76 lg/g respectively (Roy and Kumari, 1991). Analysis of herbal medicines used for liver diseases, showed presence of aflatoxins in 46% of the 50 samples tested. Sample of Asparagus racemosus was reported to contain the highest level of AFB1 (2.23 lg/g) (Kumar and Roy, 1993). The situation can be considered alarming as the medicines used for liver disorders are themselves containing hepatotoxins in high amounts. In Turkey, aflatoxin contamination in dried figs has been reported. In a recent study, dried figs samples collected from different local stores and exporting companies were examined for aflatoxin contamination by reverse phase High-performance Liquid Chromatography (HPLC) (Bircan and Koç, 2012). Higher incidence of aflatoxin contamination was reported in local store samples i.e. 47.5% of 219 samples analyzed as compared to the samples intended for export (23.6% of the 2461 samples analyzed). The aflatoxin concentration in domestic market samples was found up to 267.48 ng/g and in export samples up to 278.04 ng/g. Aflatoxin contamination of dried figs was also reported in another study from Turkey (Boyacioglu and Gonul, 1990). Average levels of 112.3 ng/g AFB1, 50.6 ng/g AFB2 and 61.4 ng/g AFG1 were detected. Another report showed co-occurrence of aflatoxins and cyclopiazonic acid in 23% samples of dried figs (Heperkan et al., 2012). Iamanaka et al. (2007) detected aflatoxins in 58% samples of dried figs at levels of 0.3–2.0 lg/kg and one sample had extremely high concentration of AFB1 (1500 lg/kg). Traditional Chinese herbal medicines have been analyzed for occurrence of aflatoxins. Yang et al. (2005) demonstrated the occurrence of AFs (up to 32 lg/kg) in 3 of 19 samples of traditional Chinese herbal medicines and Semen Platycladi was observed to contain high contamination levels. In a recent study, 174 medicinal herb samples from Chinese and international suppliers were analyzed for total aflatoxins contamination by High-performance Liquid Chromatography-Tandem Mass Spectrometry (Liu et al., 2012); 15.5% samples were tested positive for aflatoxins with concentrations up to 290.8 lg/kg and 5.71% of the positive samples exceeded the limits proposed by the authors. They suggested fat or fatty oil rich herbs should be cautiously monitored as such herbs might be more favorable for mould growth. However in another study only 5.2% medicinal herbs samples from China were

Table 1 Maximum recommended levels of aflatoxins (AFs) and ochratoxin A (OTA) in medicinal plants. Medicinal plant category

Herbal drugs Pepper, nutmeg, turmeric, ginger Dried figs

Maximum recommended levels of aflatoxins (lg/kg) AFB1

Total AFs

2 5 6

4 10 10

Reference

EP (2011) EU (2010a) EU (2012a)

Maximum recommended levels of OTA (lg/kg) Licorice root Pepper, nutmeg, turmeric, ginger

20 15

EU (2010b) and EP (2011) EU (2012b)



confirmed positive for aflatoxins (Zhang et al., 2005). A method was developed by Han et al. (2011) for detection of five aflatoxins i.e. B1, B2, G1, G2, M1 in Chinese medicines and medicinal herbs by immunoaffinity extraction coupled with ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/ MS). The method is reported to be accurate and sensitive which can be used for other complex matrices similar to medicinal herbs. Studies from Nigeria, Malaysia, Oman, Indonesia, Thailand and other countries have also reported occurrence of AFs in medicinal plants. In southern Nigeria, commonly used indigenous crude herbal preparations were found contaminated with aflatoxins in the range of 0.004–0.345 lg/kg (Oyero and Oyefolu, 2009). Aflatoxin contamination (1.7–14.3 ng/g) in 5 out of 28 herbal medicinal products was reported in Thailand (Tassaneeyakul et al., 2004). Low levels of aflatoxin contamination were also detected in traditional herbal medicines from Indonesia and Malaysia (Ali et al., 2005). In South Korea, among 700 herbal medicine plants, 8.29% and 2.43% of samples were positive for AFB1 (up to 73.27 lg/kg) and total aflatoxins (108.42 lg/kg) respectively (Shim et al., 2012). In Oman, different spices were analyzed for aflatoxin and mycoflora. The predominant species were Penicillium sp., Aspergillus niger, A. flavus and Rhizopus and 45% of the A. flavus strains were aflatoxigenic. Of the 7 spices analyzed, cumin was found to be the most contaminated whereas clove was the least contaminated (Elshafie et al., 2002) and 50 samples of cinnamon (Cinnamomum zeylanicum blume) were evaluated for aflatoxins revealing contamination in 62% samples (up to 4.67 lg/kg) in Saudi Arabia (Al-juraifani, 2011). However, in Italy, all samples of medicinal plants, aromatic herbs and herbal infusions tested for aflatoxins were aflatoxin negative (Romagnoli et al., 2007). Similarly 500 herbal plant samples from Poland when analyzed for aflatoxins were considered safe (Ledzion et al., 2011). Indian senna plants (Cassia senna angustifolia) were analyzed for aflatoxin contamination by HPLC method (Muller and Basedow, 2007). Aflatoxin was detected only in the pods of the plant whereas flowers and leaves were not contaminated. Moreover the aflatoxin production was reduced by fresh neem leaf water extract (but not up to desired low concentration). Abeywickrama and Bean (1991) detected up to 500 lg/kg AFB1 in Asian medicinal plants. In another report, ginseng root samples were found contaminated with aflatoxins ranging from 15.1 to 16 ng/g (D’Ovidio et al., 2006). Aflatoxin contamination (0.04–2.0 lg/kg) was also detected in 19% of the 83 milk thistle samples analyzed. High amount of aflatoxins (49,100 lg/kg) was produced by A. parasiticus strain isolated from milk thistle herb powder (Tournas et al., 2012). Natural occurrence of AFB1 was reported in kava kava at concentration of 0.5 ng/g. However the other test samples (ginger, black cohosh, valerian, ginseng and echinacea) were tested negative for aflatoxins (Weaver and Trucksess, 2010). 8.2. Ochratoxin contamination Ochratoxin A occurrence was reported in 44% of the 57 traditional Chinese medicinal plants samples analyzed with Mongolian milk-vetch root having the highest concentration (158.7 lg/kg). 92% of the positive samples were visibly mouldy (Yang et al., 2010). In another study 51 samples of traditional Chinese medicinal plants were simultaneously analyzed for OTA and OTB revealing low ochratoxins contamination in only four samples (Han et al., 2010a). Herbs that were destined for the preparation of Ayurvedic medicines were found to be contaminated with OTA at levels up to 2.34 lg/g (Roy and Kumar, 1993). Traces of ochratoxin were detected in medicinal plant materials from Tilia grandifolia (Halt, 1998). In a study, kava-kava roots and licorice samples analyzed for OTA were found contaminated with 20 and 6 ng/g respectively

5

(Trucksess et al., 2006) while Goryacheva et al. (2007) reported OTA contamination in licorice samples above 10 lg/kg. In another report, samples of licorice root and derived products were analyzed by HPLC-fluorescence technique (Arino et al., 2007) revealing 100% samples positive for OTA and some samples found highly contaminated (up to 252.8 ng/g). In Germany, licorice root and licorice sweet samples collected from different shops and pharmacies were examined for OTA by LC/MS-MS (Liquid Chromatography-Mass Spectrometry and Liquid Chromatography-Tandem Mass Spectrometry). OTA contamination at levels ranging from 0.3 to 216 lg/kg was reported (Bresch et al., 2000). Another study from Germany also reported high levels of OTA contamination in licorice roots and products (Majerus et al., 2000). OTA was detected in 47.8% of 115 samples of dried figs at concentrations in the range of 0.12–15.31 lg/kg (Karbancıoglu-Guler and Heperkan, 2008). 8.3. Fumonisin contamination Fumonisin contamination in medicinal plants has been reported in South Africa, Germany, China and Turkey. Herbal tea and medicinal plant samples in Turkey were analyzed for fumonisins (Omurtag and Yazicioglu, 2004). Two of 115 samples were found positive for FB1 at levels of 0.160 and 1.487 lg/g. Another study in Turkey reported FB1 contamination in dried figs. 75% of the 115 samples analyzed were found contaminated with FB1 with mean value of 0.315 lg/g (Karbancıoglu-Guler and Heperkan, 2009). In South Africa, four out of thirty medicinal wild plants were found contaminated with FB1 (8–1553 lg/kg) (Sewram et al., 2006). Analysis of 16 samples of African traditional herbal medicines sold in South Africa revealed the presence of FB1 in 13 samples in the range of 14–139 lg/kg. However no sample was found contaminated with aflatoxin (Katerere et al., 2008). Martins et al. (2001) reported high contamination of FB1 in leaves of orange tree ranging from 350 to 700 lg/kg. Flowers and leaves of linden tree were also found contaminated with FB1 ranging from 20 to 200 lg/kg. However lower concentrations were detected in chamomile (20–70 lg/kg) and corn silk samples (50–150 lg/kg). Fumonisins detection in asparagus was reported in Germany (Seefelder et al., 2002) and China (Liu et al., 2005), revealing contamination levels ranging from 36.4 to 4513.7 ng/g (FB1) in 90% samples and 47 to 714 ng/g (FB1 and FB2) in 80% samples respectively. In another study, FB1 and FB2 contamination was detected in 8 samples each of normal and visibly mouldy samples (spices, aromatic herbs, medicinal herbs). Average contamination level of FB1 and FB2 was 165.9 lg/kg and 256.8 lg/kg in normal samples, and 129 lg/kg and 1745 lg/kg in visibly mouldy samples (Kong et al., 2012). Han et al. (2010b), using ultra-high-performance LC-MS/MS, developed a method for simultaneous detection of FB1, FB2 and FB3 in traditional Chinese medicines (35 samples). More than 50% samples were contaminated with fumonisins (0.58– 88.95 lg/kg); 94.4%, 77.8% and 33.3% of the positive samples were contaminated with FB1, FB2 and FB3 respectively. Of the four types of samples (seeds; rhizomes and roots; grasses and leaves; flowers) seeds were found to be the most contaminated (90%) suggesting the high oil content could have favored FB production. In a similar study, method for simultaneous determination of FB1 and FB2 in traditional Chinese medicines was developed (Xie et al., 2011). In this study 32.3% samples were found positive for total fumonisins by HPLC-tandem mass spectrometry. 8.4. Zearalenone and Deoxynivalenol contamination In China, ZEA was detected in Semen coicis (coix seeds) at concentrations in the range of 18.7–211.4 lg/kg (Zhang et al., 2011). ZEA contamination of coix seeds was also reported recently in another study in China (Kong et al., 2013). The samples were highly


6


contaminated at concentrations ranging from 68.9 to 119.6 lg/kg. Yue et al. (2010) detected occurrence of DON (17.2–50.5 lg/kg) in only 3 out of 58 samples of Chinese medicinal herbs and related products. Two samples were of coix seeds and one was Baohe pills (a Chinese patent medicine). Coix seeds have long been used in traditional Chinese medicine for treating various ailments and its extract is also commonly used for cancer treatment in China (Woo et al., 2007). A report from India revealed presence of ZEA and DON in 13.07% and 6.92% of 130 samples of medicinally important dried rhizomes and root tubers (Koul and Sumbali, 2008). 8.5. Multi-mycotoxin contamination In Spain, medicinal and aromatic herbs were analyzed for multicontamination (AF, OTA, ZEA, FBs, DON, T-2 toxin and citrinin) by ELISA (Santos et al., 2009). 100% of the 84 samples analyzed showed multi-contamination. Sage and chamomile samples were multi-contaminated with all seven mycotoxins. Sage samples were highly contaminated with AFs and OTA ranging from 23.8 to 25.2 lg/kg and 1.1 to 17.3 lg/kg respectively. In this study sage leaves, chamomile flower, valerian root, senna leaves and rhubarb samples were found to be most multi-contaminated. Multimycotoxin (FB2, HT-2, ZEA, patulin etc.) contamination was also detected in dried figs from Turkey (Senyuva and Gilbert, 2008) and Chinese herbs (Ophiopogonis, Ginseng, Radix, Campanulaceae) (Ge et al., 2011). In another study, traditional Chinese medicines were evaluated and T-2 toxin was present in only one sample out of 138 samples having a concentration of 64 ng/g (Tan et al., 2011). In a study, OTA, AFB1 and citrinin were simultaneously extracted from ten samples of black table olives by a method developed by El Adlouni et al. (2006). Quantification by HPLC revealed contamination of OTA, AFB1 and citrinin in 10, 4 and 8 samples respectively. However in Japan, 49 samples of herbal drugs analyzed by TLC showed negative results for aflatoxin, sterigmatocystin and ochratoxin A (Hitokoto et al., 1978) but Aspergillus and Penicillium species were frequently isolated from powdered herbal drugs samples out of which only one strain of A. flavus was reported aflatoxigenic. In India, samples of herbal drugs of pharmaceutical industries were analyzed for natural occurrence of mycotoxins (Chourasia, 1995). Out of 150 samples, 43% were found positive for AFB1, 6% for OTA, 6% for citrinin and 4% for ZEA. The levels of concentration were 0.05–0.91 lg/g (AFB1), 0.00–0.13 lg/g (OTA), 0.00–0.16 lg/g (citrinin) and 0.00–0.11 lg/g (ZEA). In another report aflatoxins, sterigmatocystin and citrinin were detected in important crude herbal drugs (Emblica officinalis, Terminalia belliric, Terminalia chebula) of India (Gautam and Bhadauria, 2009). AFB1 and AFG2 were present in 22.22% of Emblica officinalis (Amla fruits) samples. However samples of cinnamon, yellow mustard, Indian mustard and clove from India were found free from multi-contamination (aflatoxin, ochratoxin A, sterigmatocystin, citrinin, rubratoxin and zearalenone) (Saxena and Methrota, 1998). In Pakistan, about 30% samples of medicinal plants were found contaminated with aflatoxins and ochratoxin A; Papaver somniferum (Opium poppy), Glycyrrhiza glabra (Licorice) and Withania coagulans (Indian rennet) were most contaminated samples. More than 30% of the isolated fungal species were found toxigenic (unpublished data). Aziz et al. (1998) reported occurrence of aflatoxin (10–160 lg/ kg) and ochratoxin A (20–80 lg/kg) in spices and medicinal plant samples. Of the moulds isolated, Aspergillus parasiticus, A. flavus and A. oryzae were aflatoxigenic while A. ochraceus and Penicillium viridicatum were OTA producers. In Turkey, AFB1 and OTA contamination was analyzed in dried figs samples of two types: from local market and those for export purpose (Senyuva et al., 2005). Of the

20 domestic market samples, only one was contaminated with OTA (2 ng/g) and all were free from AFB1. In the samples intended for export, 23% and 6% were detected positive for AFB1 (up to 35.1 ng/g) and OTA (up to 26.3 ng/g) respectively. Moreover 4% samples showed co-occurrence of AFB1 and OTA. In an analysis of ginger products, aflatoxins (ranging from 1 to 31 ng/g) and OTA (ranging from 1 to 10 ng/g) were detected in 67% and 74% samples respectively. Moreover, out of 10 ginseng finished products analyzed, three were found contaminated with aflatoxins in the concentration of 0.1 ng/g and four were found contaminated with OTA in the range of 0.4–1.8 ng/g (Trucksess et al., 2007). Mycological and mycotoxicological analysis of powdered herbal samples was reported by Gautam et al. (2009). Almost 91% of the samples were contaminated with fungi in which the dominant moulds were Aspergillus and Penicillium. However, only 20.58% of the analyzed samples were contaminated with mycotoxins (total aflatoxins, sterigmatocystin, citrinin). Rizzo et al. (2004) investigated toxigenic fungi in aromatic and medicinal herbs which are utilized as raw material for drugs. 52% samples were contaminated with Aspergillus and 27% contaminated with Fusarium genus; 50% isolates were toxigenic and the mycotoxins were detected by TLC and HPLC. In another similar study, 89.9% fungal isolates obtained from medicinal plants belonged to Penicillium and Aspergillus genera of which 21.97% were toxigenic; 42.9% were aflatoxin producers and 22.4% were OTA producers (Bugno et al., 2006). The maximum concentration levels of mycotoxins in certain medicinal plants are summarized in Table 2. 9. Risk assessment studies Although numerous studies on toxicity of mycotoxins are reported, the literature is mostly silent on harmful effects by mycotoxins in medicinal plants. Effect of mycotoxins found in medicinal herbs was analyzed in mice on biochemical parameters (Alwakeel, 2009). Nephrotoxicity and hepatotoxicity was induced in mice when fed with herbal extracts and aflatoxins extracted from the herbal medicines. In another study, ZEA produced by Fusarium species, isolated from medicinal plants, were shown to cause cytotoxicity in mammalian cells (Abeywickrama and Bean, 1992). Estrogenic effects in postmenopausal women were also suspected to be due to the use of zearalenone contaminated ginseng (Gray et al., 2004). 10. Inhibitory effects of medicinal plants on mycotoxins In contrast to the worldwide problem of mycotoxin production in medicinal plants, there are also several reports of detoxification of mycotoxins by medicinal plants and their constituents. Essential oils of various medicinal plants are reported as inhibitors of mycotoxin and toxigenic fungi. Singh et al. (2008) recommended oil of Cinnamomum camphora for the inhibition of fungal growth and AFB1 production in raw materials of herbal drugs. Essential oil of Satureja hortensis L. (Razzaghi-Abyaneh et al., 2008) and Ageratum conyzoides L. (Patil et al., 2010) were reported as inhibitors of Aspergillus parasiticus growth and aflatoxin production. Similarly growth and aflatoxin production by A. flavus are inhibited by extracts of Garcinia cowa and G. pedunculata (Joseph et al., 2005); oil of Azadirachta indica (Bankole, 1997) and Cymbopogon citratus (Paranagama et al., 2003). Production of fumonisin B1 and aflatoxins by mycotoxigenic fungi is reduced by extracts of Citrus sinensis (Mohanlall and Odhav, 2006). Several studies conducted on animals reveal the protective effects of medicinal plants on toxicity of aflatoxins. Various


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S. Ashiq et al. / Fungal Genetics and Biology xxx (2014) xxx–xxx Table 2 Incidence of mycotoxins in medicinal plants and products, based on literature.

a

Medicinal plant category

Country of origin

Type of mycotoxin

Maximum concentration of mycotoxina (lg/kg)

Reference

Chamomile Asparagus Ginger products Black table olives Dried figs Medicinal herbs (general) Crude herbal preparations Herbal medicinal products Ginseng products Medicinal herbs (general) Cinnamon Herbal drugs Ginseng root Milk thistle supplements Kava kava Sage Rosehip Ginseng products Mongolian milk-vetch root Ayurvedic medicine preparations Kava kava Black table olives Herbal drugs Licorice Ginger products Sage Licorice root and licorice sweets Dried figs Licorice Medicinal wild plants Chamomile Medicinal plants (general) Dried figs Asparagus African traditional herbal medicine Corn silk Asparagus Traditional Chinese medicine Orange tree leaves Flowers and leaves of linden tree Coix seeds Herbal drugs Chinese medicinal herbs Coix seeds Traditional Chinese medicines Herbal drugs

Turkey India USA Morocco Turkey China Nigeria Thailand USA South Korea Saudi Arabia India USA USA USA Spain Turkey USA China India USA Morocco India Spain USA Spain Germany Turkey USA South Africa Portugal Turkey Turkey Germany South Africa Portugal China China Portugal Portugal China India China China China India

AFB1 AFB1 AFs AFB1 AFs AFs AFs AFs AFs AFB1 AFs AFB1 AFs AFs AFB1 AFs AFB1 OTA OTA OTA OTA OTA OTA OTA OTA OTA OTA OTA OTA FB1 FB1 FB1 FB1 FB1 FB1 FB1 FB1, FB2 FB1,FB2,FB3 FB1 FB1 ZEA ZEA DON ZEA T2 toxin Citrinin

38.9 2230.0 31.0 5.0 278.04 290.8 0.345 14.3 0.1 73.27 4.67 910.0 16.0 2.0 0.5 25.2 52.5 1.8 158.7 2340.0 20.0 0.65 130.0 252.8 10.0 17.3 216.0 15.31 6.0 1553.0 70.0 1487.0 3649.0 4513.7 139.0 150.0 714.0 88.95 700.0 200.0 119.6 110.0 50.5 211.4 64.0 160.0

Tosun and Arslan (2013) Kumar and Roy (1993) Trucksess et al. (2007) El Adlouni et al. (2006) Bircan and Koç (2012) Liu et al. (2012) Oyero and Oyefolu (2009) Tassaneeyakul et al. (2004) Trucksess et al. (2007) Shim et al. (2012) Al-juraifani (2011) Chourasia (1995) D’Ovidio et al. (2006) Tournas et al. (2012) Weaver and Trucksess (2010) Santos et al. (2009) Tosun and Arslan (2013) Trucksess et al. (2007) Yang et al. (2010) Roy and Kumar (1993) Trucksess et al. (2006) El Adlouni et al. (2006) Chourasia (1995) Arino et al. (2007) Trucksess et al. (2007) Santos et al. (2009) Bresch et al. (2000) Karbancıoglu-Guler and Heperkan (2008) Trucksess et al. (2006) Sewram et al. (2006) Martins et al. (2001) Omurtag and Yazicioglu (2004) Karbancıoglu-Guler and Heperkan (2009) Seefelder et al. (2002) Katerere et al. (2008) Martins et al. (2001) Liu et al. (2005) Han et al. (2010b) Martins et al. (2001) Martins et al. (2001) Kong et al. (2013) Chourasia (1995) Yue et al. (2010) Zhang et al. (2011) Tan et al. (2011) Chourasia (1995)

Maximum contamination level of mycotoxin detected in samples.

medicinal plants are reported to significantly reduce AFB1 hepatotoxicity in rats, such as, date, Nigella sativa (Al-Ghasham et al., 2008), garlic (Sheen et al., 2001), Schisandra chinensis (Ip et al., 1996) and Thonningia sanguinea (Gyamfi and Aniya, 1998). Kolaviron (biflavonoid from Garcinia kola seeds) was tested by Nwankwo et al. (2000) to have potential of inhibiting AFB1 genotoxicity in human by experimenting on human liver derived HepG2 cells. Studies on the preventive effects of medicinal plant extracts against carcinogenesis are found in literature. Extracts of Ginkgo biloba (Hao et al., 2009) and garlic (el-Mofty et al., 1994) are found to be effective against AFB1 induced hepatocarcinogenesis. 11. Conclusions On basis of this review, it is obvious that medicinal plants and related products that are commercially available can be contaminated with mycotoxins at levels exceeding regulations in some countries, so the need to detect mycotoxin contamination in

medicinal plants is apparent and strategies should be developed and applied to prevent formation of mycotoxin. Maximum limits of common mycotoxins should be officially specified for various medicinal plants and their products. It is necessary to further investigate the presence of mycotoxins in these commodities. Plant materials, destined for medical uses, should be carefully stored and evaluated for mycotoxin presence before use in order to ensure they are safe for consumers. The kind and quantity of medicinal plants taken by the consumer varies with the health condition for which it is consumed, so the concentration levels of mycotoxin that humans are exposed to by the intake of medicinal plants needs to be considered for every type of medicinal plant individually. Moreover, moulds isolated from medicinal plant materials were reported by various studies to have toxigenic potential, therefore to protect consumers against mycotoxin health hazards, storage conditions should be improved and good agricultural practice should be implemented to lower the presence of moulds on the medicinal plants and thus reduce the possibility of mycotoxin production.


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References Abarca, M.L., Accensi, F., Bragulat, M.R., Cabañes, F.J., 2001. Current importance of ochratoxin A-producing Aspergillus spp.. J. Food Prot. 64, 903–906. Abeywickrama, K., Bean, G.A., 1991. Toxigenic Aspergillus flavus and aflatoxins in Sri-Lankan medicinal plant material in USA. Mycopathologia 113, 187–190. Abeywickrama, K., Bean, G.A., 1992. Cytotoxicity of Fusarium species, mycotoxins and culture filtrates of Fusarium species isolated from the medicinal plant Tribulus terrestris to mammalians cells. Mycopathologia 120, 189–193. Abou Donia, M.A., 2008. Microbiological Quality and Aflatoxinogenesis of Egyptian Spices and Medicinal Plants. Global Vet. 2 (4), 175–181. Abou-Arab, A.A.K., Kawther, M.S., El Tantawy, M.E., Badeaa, R.I., Khayria, N., 1999. Quantity estimation of some contaminants in commonly used medicinal plants in the Egyptian market. Food Chem. 67, 357–363. Al-Ghasham, A., Ata, H.S., El-Deep, S., Meki, A.R., Shehada, S., 2008. Study of protective effect of date and Nigella Sativa on Aflatoxin B1 toxicity. Int. J. Health Sci. (Qassim) 2 (2), 26–44. Ali, N., Hashim, N.H., Saad, B., Safan, K., Nakajima, M., Yoshizawa, T., 2005. Evaluation of a method to determine the natural occurrence of aflatoxins in commercial traditional herbal medicines from Malaysia and Indonesia. Food Chem. Toxicol. 43, 1763–1772. Al-juraifani, A.A., 2011. Natural occurrence of fungi and aflatoxins of cinnamon in the Saudi Arabia. Afr. J. Food Sci. 5 (8), 460–465. Alwakeel, S.S., 2009. The effect of mycotoxins found in some herbal plants on biochemical parameters in blood of female albino mice. Pak. J. Biol. Sci. 12 (8), 637–642. Arino, A., Herrera, M., Estopanan, G., Juan, T., 2007. High levels of ochratoxin A in licorice and derived products. Int. J. Food Microbiol. 114, 366–369. Astin, J.A., 1998. Why patients use alternative medicine: results of a national study. JAMA, J. Am. Med. Assoc. 279, 1548–1553. Aziz, N.H., Youssef, Y.A., El-Fouly, M.Z., Moussa, L.A., 1998. Contamination of some medicinal plant samples and spices by fungi and their mycotoxins. Bot. Bull. Acad. Sin. 39, 279–285. Bankole, S.A., 1997. Effects of essential oil from two Nigerian medicinal plants (Azadirachta indica and Morinda lucida) on growth and aflatoxin B1 production in maize grain by a toxigenic Aspergillus flavus. Lett. Appl. Microbiol. 24, 190– 192. Bennett, J.W., Klich, M., 2003. Mycotoxins. Clin. Microbiol. Rev. 16, 497–516. Bhatnagar, D., Ehrlich, K.C., Cleveland, T.E., 2003. Molecular genetic analysis and regulation of aflatoxin biosynthesis. Appl. Microbiol. Biotechnol. 61 (2), 83–93. Bircan, C., Koç, M., 2012. Aflatoxins in dried figs in Turkey: a comparative survey on the exported and locally consumed dried figs for assessment of exposure. J. Agric. Sci. Technol. (Tehran, Islamic Re pub. Iran) 14, 1265–1274. Boyacioglu, D., Gonul, M., 1990. Survey of aflatoxin contamination of dried figs grown in Turkey in 1986. Food Addit. Contam. 7, 235–237. Brera, C., Miraglia, M., Colatosti, M., 1998. Evaluation of the impact of mycotoxins on human health: sources of errors. Microchem. J. 5, 45–49. Bresch, H., Urbanek, M., Nusser, M., 2000. Ochratoxin A in food containing liquorice. Nahrung 44, 276–278. Bugno, A., Almodovar, A.A.B., Pereira, T.C., Pinto, T.J.A., Sabino, M., 2006. Occurrence of toxigenic fungi in herbal drugs. Braz. J. Microbiol. 37, 47–51. Busby, W.F., Wogan, G.N., 1984. Aflatoxins. Chemical carcinogens. ACS Monogr. 2, 945–1136. Cabañes, F.J., Bragula, M.R., Castellá, G., 2010. Ochratoxin A species in the genus Penicillium. Toxins 2, 1111–1120. Calixto, J.B., 2000. Efficacy, safety, quality control, marketing and regulatory guidelines for herbal medicines (phytotherapeutic agents). Braz. J. Med. Biol. Res. 33, 179–189. Chan, K., 2003. Some aspects of toxic contaminants in herbal medicines. Chemosphere 52 (9), 1361–1371. Chourasia, H.K., 1995. Mycobiota and mycotoxins in herbal drugs of Indian pharmaceutical industries in India. Mycol. Res. 99 (6), 697–703. Coppock, R.W., Swanson, S.P., Gelberg, H.B., Koritz, G.D., Hoffman, W.E., Buck, W.B., Vesonder, R.F., 1985. Preliminary study of the pharmacokinetics and toxicopathy of deoxynivalenol (vomitoxin) in swine. Am. J. Vet. Res. 46, 169– 174. Cowan, M.M., 1999. Plant products as antimicrobial agents. Clin. Microbiol. Rev. 12 (4), 564–582. D’Ovidio, K., Trucksess, M., Weaver, C., Horn, E., McIntosh, M., Bean, G., 2006. Aflatoxins in ginseng roots. Food Addit. Contam. 23 (2), 174–180. EC, 2006. European Commission Regulation (EC) No. 1881/2006 of 19 December 2006 setting maximum levels for certain contaminants in foodstuffs, 2006. Off. J. Eur. Union L, vol. 364, pp. 5–24. EC, 2007. European Commission Regulation (EC) No. 1126/2007 of 28 September 2007 amending Regulation (EC) No 1881/2006 setting maximum levels for certain contaminants in foodstuffs as regards Fusarium toxins in maize and maize products. Off. J. Eur. Union L, vol. 255, pp. 14–17. EHC, 2000. In: Marasas, W.H.O., Miller, J.D., Riley, R.T., Visconti, A. (Eds.), Environmental Health Criteria 219, Fumonisin B1, International Programme on Chemical Safety (IPCS; UNEP, ILO and WHO). WHO, Geneva. El Adlouni, C., Tozlovanu, M., Naman, F., Faid, M., Pfohl-Leszkowicz, A., 2006. Preliminary data on the presence of mycotoxins (ochratoxin A, citrinin and aflatoxin B1) in black table olives ‘‘Greek style’’ of Moroccan origin. Mol. Nutr. Food Res. 50, 507–512.

El-Hoshy, S.M., 1999. Occurence of zearalenone in milk, meat and their products with emphasis on influence of heat treatments on its level. Arch. Lebensmittelhyg 50, 140–143. el-Mofty, M.M., Sakr, S.A., Essawy, A., Abdel Gawad, H.S., 1994. Preventive action of garlic on aflatoxin B1-induced carcinogenesis in the toad Bufo regularis. Nutr. Cancer 21 (1), 95–100. Elshafie, A.E., Al-Rashdi, T.A., Al-Bahry, S.N., Bakheit, C.S., 2002. Fungi and aflatoxins associated with spices in the Sultanate of Oman. Mycopathologia 155 (3), 155– 160. EMAN, 2003. European Mycotoxin Awareness Network co-ordinated by Leatherhead Food Research Association (UK), 2003. . EP (European Pharmacopoeia), 2011. Council of Europe. European Directorate for the Quality of Medicines (EDQM), 7th ed. Eriksen, G.S., Alexander, J. (Eds.), 1998. Fusarium Toxins in Cereals – A Risk Assessment. Nordic Council of Ministers; Tema Nord 502, pp. 7–27 and 45–58; Copenhagen. EU, 2010a. European Union Commission Regulation (EU) No. 165/2010 of 26 February 2010 amending Regulation (EC) No 1881/2006 setting maximum levels for certain contaminants in foodstuffs as regards aflatoxins. Off. J. Eur. Union L, vol. 50, pp. 8–12. EU, 2010b. European Union Commission Regulation (EU) No. 105/2010 of 5 February 2010 amending Regulation (EC) No 1881/2006 setting maximum levels for certain contaminants in foodstuffs as regards ochratoxin A. Off. J. Eur. Union L, vol. 35, pp. 7–8. EU, 2012a. European Union Commission Regulation (EU) No. 1058/2012 of 12 November 2012 amending Regulation (EC) No. 1881/2006 as regards maximum levels for aflatoxins in dried figs. Off. J. Eur. Union L, vol. 313, pp. 14–15. EU, 2012b. European Union Commission Regulation (EU) No 594/2012 of 5 July 2012 amending Regulation (EC) 1881/2006 as regards the maximum levels of the contaminants ochratoxin A, non dioxin-like PCBs and melamine in foodstuffs. Off. J. Eur. Union L, vol. 176, pp.43–45. FAO (Food and Agriculture Organization of United Nations), 1997. Legislative maximum tolerated levels of Aflatoxin and regulatory guidelines of other mycotoxin in some foodstuffs, feedstuffs and dairy products, from worldwide regulations for mycotoxins. FAO Food and Nutrition Paper 64, pp. 20–25. FAO (Food and Agriculture Organization of United Nations), 2001. Manual on the Application of the HACCP System in Mycotoxin Prevention and Control, 73, FAO Food and Nutrition Paper, Rome. FAO (Food and Agriculture Organization of United Nations), 2003. FAO corporate repository, Economic and Social Department Worlwide regulations for mycotoxins in food and feed in 2003. Mycotoxin regulations in 2003 and current developments, pp. 1–20. FAO (Food and Agriculture Organization of United Nations), 2004. Worldwide regulations for mycotoxins in food and feed in 2003. FAO Food and Nutrition Paper 81. Rome, Italy: Food and Agriculture Organization of the United Nations. Forsell, J.H., Jensen, R., Tai, J.H., Witt, M., Lin, W.S., Pestka, J.J., 1987. Comparison of acute toxicities of deoxynivalenol (vomitoxin) and 15-acetyldeoxynivalenol in the B6C3F1 mouse. Food Chem. Toxicol. 25, 155–162. Gao, H.P., Yoshizawa, T., 1997. Further study on Fusarium mycotoxins in corn and wheat from a high-risk area for human esophageal cancer in China. Mycotoxins 45, 51–55. Gaumy, J.L., Bailly, J.D., Ernard, G., Guerre, P., 2001. Zearalenone: Origin and effects on farm animals. Rev. Med. Vet. (Toulouse, Fr.) 152, 123–136. Gautam, A.K., Bhadauria, R., 2009. Mycoflora and mycotoxins in some important stored crude and powdered herbal drugs. Biol. Forum Int. J. 1 (1), 1–7. Gautam, A.K., Sharma, S., Bhadauria, R., 2009. Detection of toxigenic fungi and mycotoxins in medicinally important powdered herbal drugs. Internet J. Microbiol. 7 (2). Ge, B., Zhao, K., Wang, W., Mi, J., 2011. Determination of 14 mycotoxins in Chinese herbs by liquid chromatography-tandem mass spectrometry with immunoaffinity purification. Se Pu 29 (6), 495–500. Ghani, A., 1998. Medicinal plants of Bangladesh: Chemical Constituents and Uses, first ed. Asiatic Society of Bangladesh, Dhaka, p. 224. Goryacheva, I.Y., Saeger, D.S., Nesterenko, I.S., Eremin, S.A., Peteghem, C.V., 2007. Rapid all-in-one three-step immunoassay for non-instrumental detection of ochratoxin A in high-coloured herbs and spices. Talanta 72, 1230–1234. Gray, S.L., Lackey, B.R., Tate, P.L., Riley, M.B., Camper, N.D., 2004. Mycotoxins in root extracts of American and Asian ginseng bind estrogen receptors alpha and beta. Exp. Biol. Med. 229, 560–568. Groopman, J.D., Kensler, W., 1996. Temporal patterns of aflatoxin albumin adducts in hepatitis B surface antigen-positive and antigen negative residents of Daxin, Qidong County, People’s Republic of China. Cancer Epidemiol., Biomarkers Prev. 5 (4), 253–261. Gyamfi, M.A., Aniya, Y., 1998. Medicinal herb, Thonningia sanguinea protects against aflatoxin B1 acute hepatotoxicity in Fischer 344 rats. Hum. Exp. Toxicol. 17 (8), 418–423. Halt, M., 1998. Moulds and mycotoxins in herb tea and medicinal plants. Eur. J. Epidemiol. 14, 269–274. Han, Z., Ren, Y., Liu, X., Luan, L., Wu, Y., 2010a. A reliable isotope dilution method for simultaneous determination of fumonisins B1, B2 and B3 in traditional Chinese medicines by ultra-high-performance liquid chromatography-tandem mass spectrometry. J. Sep. Sci. 33, 2723–2733. Han, Z., Zheng, Y., Luan, L., Ren, Y., Wua, Y., 2010b. Analysis of ochratoxin A and ochratoxin B in traditional Chinese medicines by ultra-high-performance liquid


S. Ashiq et al. / Fungal Genetics and Biology xxx (2014) xxx–xxx chromatography–tandem mass spectrometry using [13C20]-ochratoxin A as an internal standard. J. Chromatogr., A 1217, 4365–4374. Han, S., Liu, Y., Lu, M., Li, J., Wang, J., 2011. Determination of five aflatoxins in Chinese patent medicines and medicinal herbs by immunoaffinity extraction coupled with ultra-high performance liquid chromatography-tandem mass spectrometry. Se Pu 29 (7), 613–617. Hao, Y.R., Yang, F., Cao, J., Ou, C., Zhang, J.J., Yang, C., Duan, X.X., Li, Y., Su, J.J., 2009. Ginkgo biloba extracts (EGb761) inhibits aflatoxin B1-induced hepatocarcinogenesis in Wistar rats. Zhong Yao Cai 32 (1), 92–96. Heperkan, D., Somuncuoglu, S., Karbancioglu-Güler, F., Mecik, N., 2012. Natural contamination of cyclopiazonic acid in dried figs and co-occurrence of aflatoxin. Food Control 23, 82–86. Hewitt, T.C., Flack, C.L., Kolodziejczyk, J.K., Chacon, A.M., D’Ovidio, K.L., 2012. Occurrence of zearalenone in fresh corn and corn products collected from local Hispanic markets in San Diego County, CA. Food Control 26, 300–304. Hitokoto, H., Morozumi, S., Wauke, T., Sakai, S., Kurata, H., 1978. Fungal contamination and mycotoxin detection of powdered herbal drugs. Appl. Environ. Microbiol. 36 (2), 252–256. Hopmans, E.C., Murphy, P.A., 1993. Detection of fumonisins B1, B2 and B3 and hydrolyzed fumonisin B1 in corn-containing foods. J. Agric. Food Chem. 41, 1655–1658. Hussein, S.H., Brasel, J.M., 2001. Toxicity, metabolism and impact of mycotoxins on humans and animals. Toxicology 167, 101–134. Iamanaka, B.T., de Menezes, H.C., Vicente, E., Leite, R.S.F., Taniwaki, M.H., 2007. Aflatoxigenic fungi and aflatoxins occurrence in sultanas and dried figs commercialized in Brazil. Food Control 18, 454–457. IARC (International agency for research on cancer), 1993. Monographs on the evaluation of the carcinogenic risk of chemicals to humans: Some naturally occurring substances: Food Items and Constituents, Heterocyclic Aromatic Amines and Mycotoxins, vol. 56, pp. 245–521. Lyon, France. Ip, S.P., Mak, D.H., Li, P.C., Poon, M.K., Ko, K.M., 1996. Effect of a lignan-enriched extract of Schisandra chinensis on aflatoxin B1 and cadmium chloride-induced hepatotoxicity in rats. Pharmacol. Toxicol. 78 (6), 413–416. Iqbal, S.Z., Bhatti, I.A., Asi, M.R., Bhatti, H.N., Sheikh, M.A., 2011. Aflatoxin contamination in chilies from Punjab Pakistan with reference to climate change. Int. J. Agric. Biol. 13, 261–265. Janati, S.S.F., Beheshti, H.R., Asadi, M., Mihanparast, S., Feizy, J., 2012. Preliminary Survey of Aflatoxins and Ochratoxin A in Dried Fruits from Iran. Bull. Environ. Contam. Toxicol. 88, 391–395. JECFA, 2000. Joint FAO/WHO Expert Committee on Food Additives, 53rd Report. Safety evaluation of certain food additives and contaminants, WHO Food Additives Series 44. IPCS – International Programme on Chemical Safety. WHO, Geneva. Joseph, G.S., Jayaprakasha, G.K., Selvi, A.T., Jena, B.S., Sakariah, K.K., 2005. Antiaflatoxigenic and antioxidant activities of Garcinia extracts. Int. J. Food Microbiol. 101, 153–160. Karbancıoglu-Guler, F., Heperkan, D., 2008. Natural occurrence of ochratoxin A in dried figs. Anal. Chim. Acta 617, 32–36. Karbancıoglu-Guler, F., Heperkan, D., 2009. Natural occurrence of fumonisin B1 in dried figs as an unexpected hazard. Food Chem. Toxicol. 47, 289–292. Katerere, D.R., Stockenström, S., Thembo, K.M., Rheeder, J.P., Shephard, G.S., Vismer, H.F., 2008. A preliminary survey of mycological and fumonisin and aflatoxin contamination of African traditional herbal medicines sold in South Africa. Hum. Exp. Toxicol. 27 (11), 793–798. Kong, W., Xie, T., Li, J., Wei, J., Qiu, F., Qi, A., Zheng, Y., Yang, M., 2012. Analysis of fumonisins B1 and B2 in spices and aromatic and medicinal herbs by HPLC-FLD with on-line post-column derivatization and positive confirmation by LC-MS/ MS. Analyst 137, 3166–3174. Kong, W.J., Shen, H.H., Zhang, X.F., Yang, X.L., Qiu, F., Ou-yang, Z., Yang, M.H., 2013. Analysis of zearalenone and a-zearalenol in 100 foods and medicinal plants determined by HPLC-FLD and positive confirmation by LC–MS–MS. J. Sci. Food Agric. 93 (7), 1584–1590. Koul, A., Sumbali, G., 2008. Detection of zearalenone, zearalenol and deoxynivalenol from medicinally important dried rhizomes and root tubers. Afr. J. Biotechnol. 7 (22), 4136–4139. Kuiper-Goodman, T., Scott, P.M., Watanabe, H., 1987. Risk assessment of the mycotoxin zearalenone. Regul. Toxicol. Pharmacol. 7, 253–306. Kumar, S., Roy, A.K., 1993. Occurrence of aflatoxin in some liver curative herbal medicines in India. Lett. Appl. Microbiol. 17 (3), 112–114. Ledzion, E., Rybin´ska, K., Postupolski, J., Kurpin´ska-Jaworska, J., Szczesna, M., 2011. Studies and safety evaluation of aflatoxins in herbal plants. Rocz Panstw Zakl Hig 62 (4), 377–381. Leeson, S., Diaz, G.J., Summers, J.D., 1995. Poultry Metabolic Disorders and Mycotixns. University Books, Guelph, Ontario, Canada, pp. 249–298. Li, S., Marquardt, R.R., Frohlich, A.A., Vitti, T.G., Crow, G., 1997. Pharmacokinetics of ochratoxin A and its metabolites in rats. Toxicol. Appl. Pharmacol. 145, 82. Liu, C., Liu, F., Xu, W., Kofoet, A., Humpf, H., Jiang, S., 2005. Occurrence of fumonisins B1 and B2 in asparagus from Shandong province. Food Addit. Contam. 22, 673–676. Liu, L., Jin, H., Sun, L., Ma, S., Lin, R., 2012. Determination of Aflatoxins in Medicinal Herbs by High-performance Liquid Chromatography-Tandem Mass Spectrometry. Phytochem. Anal. 23, 469–476. Logrieco, A., Mule, G., Moretti, A., Bottalico, A., 2002. Toxigenic Fusarium species and mycotoxins associated with maize ear rot in Europe. Eur. J. Plant Pathol. 108, 597–609.

9

Magnoli, C., Hallak, C., Astoreca, A., Ponsone, L., Chiacchiera, S., Dalcero, A.M., 2006. Occurrence of ochratoxin A producing fungi in commercial corn kernels in Argentina. Mycopathologia 161, 53–58. Majerus, P., Max, M., Klaffke, H., Plavinskas, R., 2000. Ochratoxin A in Subholz, Lakritze und daraus hergestellten Erzeugnissen. Deustche LebensmittelRundschau 96, 451–454. Martins, M.L., Martins, H.M., Bernardo, F., 2001. Fumonisins B1 and B2 in black tea and medicinal plants. J. Food Prot. 64, 1268–1270. Miller, J.D., 1995. Fungi and mycotoxins in grain: implications for stored product research. J. Stored Prod. Res. 31, 1–6. Ministry of Health of the People’s Republic of China, 2005. Hygienic Standard for Grains. GB2751-2005. Beijing: Ministry of Health of the People’s Republic of China. Mohanlall, V., Odhav, B., 2006. Biocontrol of aflatoxins B1, B2, G1, G2, and fumonisin B1 with 6,7-dimethoxycoumarin, a phytoalexin from Citrus sinensis. J. Food Prot. 69 (9), 2224–2229. Muller, P., Basedow, T., 2007. Aflatoxin contamination of pods of Indian Cassia senna L. (caesalpinaceae) before harvest, during drying and in storage: reasons and possible methods of reduction. J. Stored Prod. Res. 43, 323–329. Myburg, R.B., Dutton, M.F., Chuturgoon, A.A., 2002. Cytotoxicity of Fumonisin B1, Diethylnitrosamine, and Catechol on the SNO Esophageal Cancer Cell Line. Environ. Health Perspect. 110 (8), 813–815. Nwankwo, J.O., Tahnteng, J.G., Emerole, G.O., 2000. Inhibition of aflatoxin B1 genotoxicity in human liver-derived HepG2 cells by kolaviron biflavonoids and molecular mechanisms of action. Eur. J. Cancer Prev. 9 (5), 351–361. Omurtag, G.Z., Yazicioglu, D., 2004. Determination of fumonisin B1 and B2 in herbal tea and medicinal plants in Turkey by high performance liquid chromatography. J. Food Prot. 67, 1782–1786. Oyero, O.G., Oyefolu, A.O.B., 2009. Fungal contamination of crude herbal remedies as a possible source of mycotoxin exposure in man. Asian Pac. J. Trop. Med. 2 (5), 38–43. Paranagama, P.A., Abeysekera, K.H.T., Abeywickrama, K., Nugaliyadde, L., 2003. Fungicidal and anti-aflatoxigenic effects of the essential oil of Cymbopogon citratus (DC.) Stapf. (lemongrass) against Aspergillus flavus Link. isolated from stored rice. Lett. Appl. Microbiol. 37, 86–90. Passone, M.A., Rosso, L.C., Ciancio, A., Etcheverry, M., 2010. Detection and quantification of Aspergillus section Flavi spp. in stored peanuts by real-time PCR of nor-1 gene, and effects of storage conditions on aflatoxin production. Int. J. Food Microbiol. 138, 276–281. Patil, R.P., Nimbalkar, M.S., Jadhav, U.U., Dawkar, V.V., Govindwar, S.P., 2010. Antiaflatoxigenic and antioxidant activity of an essential oil from Ageratum conyzoides L. J. Sci. Food Agric. 90, 608–614. Pena, A., Seifrtová, M., Lino, C., Silveira, I., Solich, P., 2006. Estimation of ochratoxin A in Portuguese population: new data on the occurrence in human urine by high performance liquid chromatography with fluorescence detection. Food Chem. Toxicol. 44, 1449–1454. Petzinger, E., Ziegler, K., 2000. Ochratoxin A from a toxicological perspective. J. Vet. Pharmacol. Ther. 23, 91–98. Pfohl-Leszkowicz, A., Manderville, R.A., 2007. Ochratoxin A: an overview on toxicity and carcinogenicity in animals and humans. Mol. Nutr. Food Res. 51, 61–99. Pitt, J.I., 1996. What are mycotoxins? Aust. Mycotoxin Newslett. 7, 1. Razzaghi-Abyaneh, M., Shams-Ghahfarokhi, M., Yoshinari, T., Rezaee, M.-B., Jaimand, K., Nagasawa, H., Sakuda, S., 2008. Inhibitory effects of Satureja hortensis L. essential oil on growth and aflatoxin production by Aspergillus parasiticus. Int. J. Food Microbiol. 123, 228–233. Rheeder, J.P., Sydenham, E.W., Marasas, W.F.O., Thiel, P.G., Shepherd, G.S., van Schalkwyk, D.J., 1992. Fusarium moniliforme and fumonisins in corn in relation to human oesophageal cancer in Transkei. Phytopathology 82, 353–357. Rheeder, J.P., Marasas, W.F.O., Wismer, H.F., 2002. Production of fumonisin analogs by Fusarium species. Appl. Environ. Microbiol. 68, 2101–2105. Richard, J.L., 2007. Some major mycotoxins and their mycotoxicoses: an overview. Int. J. Food Microbiol. 119, 3–10. Rizzo, I., Vedoya, G., Maurutto, S., Haidukowski, M., Varsavsky, E., 2004. Assessment of toxigenic fungi on Argentinean medicinal herbs. Microbiol. Res. 159 (2), 113– 120. Romagnoli, B., Menna, V., Gruppioni, N., Bergamini, C., 2007. Aflatoxins in spices, aromatic herbs, herb-teas and medicinal plants marketed in Italy. Food Control 18 (6), 697–701. Rotter, B.A., Prelusky, D.B., Pestka, J.J., 1996. Toxicology of deoxynivalenol (vomitoxin). J. Toxicol. Environ. Health 48, 1–34. Roy, A.K., Chourasia, H.K., 1989. Aflatoxin Problems in Some Medicinal Plants under Storage. Int. J. Crude Drug Res. 27 (3), 156–160. Roy, A.K., Kumar, S., 1993. Occurrence of ochratoxin A in herbal drugs of. Indian origin – a report. Mycotoxin Res. 9, 94–98. Roy, A.K., Kumari, V., 1991. Aflatoxin and citrinin in seeds of some medicinal plants under storage. Int. J. Pharmacogn. 29, 62–65. Roy, A.K., Sinha, K.K., Chourasia, H.K., 1988. Aflatoxin contamination of some common drug plants. Appl. Environ. Microbiol. 54, 842–843. Saenz de Rodriguez, C.A., Bongiovanni, A.M., Conde de Borrego, L., 1985. An epidemic of precocious development in Puerto Rican children. J. Pediatr. 107, 393–396. Sanchis, V., Magan, N., 2004. Environmental conditions affecting mycotoxins. In: Magan, N., Olsen, M. (Eds.), Mycotoxin in Food. Detection and Control. CRC Press, Boca Raton Boston, New York, Washington, DC, pp. 307–338.


10


Santos, L., Marin, S., Sanchis, V., Ramos, A.J., 2009. Screening of mycotoxin multicontamination in medicinal and aromatic herbs sampled in Spain. J. Sci. Food Agric. 89, 1802–1807. Sardiñas, N., Vázquez, C., Gil-Serna, J., Gónzalez-Jaén, M.T., Patiño, B., 2011. Specific detection and quantification of Aspergillus flavus and Aspergillus parasiticus in wheat flour by SYBR Green quantitative PCR. Int. J. Food Microbiol. 145, 121–125. Saxena, J., Methrota, B.S., 1998. Screening of spices commonly marketed in India for natural occurrence of mycotoxins. J. Food Compos. Anal. 2, 286–292. Scaff, R.M.C., Scussel, V.M., 2004. Fumonisins B1 and B2 in corn-based products commercialized in the State of Santa Catarina-Southern Brazil. Braz. Arch. Biol. Technol. 47, 911–919. Schoental, R., 1983. Precocious sexual development in Puerto Rico and oestrogenic mycotoxins (zearalenone). Lancet 1, 537. Seefelder, W., Gossmann, M., Humpf, H.U., 2002. Analysis of fumonisin B1 in Fusarium proliferatum-infected asparagus spears and garlic bulbs from Germany by liquid chromatography-electrospray ionization mass spectrometry. J Agric Food Chem. 50 (10), 2778–2781. Selim, M.I., Popendorf, W., Ibrahim, M.S., El Sharkawy, S., El Kashory, E.S., 1996. Aflatoxin B1 in common Egyptian foods. J. AOAC Int. 79 (5), 1124–1129. Senyuva, H.Z., Gilbert, J., 2008. Identification of fumonisin B2, HT-2 toxin, patulin, and zearalenone in dried figs by liquid chromatography-time-of-flight mass spectrometry and liquid chromatography-mass spectrometry. J. Food Prot. 71 (7), 1500–1504. Senyuva, H.Z., Gilbert, J., Ozcan, S., Ulken, U., 2005. Survey for co-occurrence of ochratoxin A and aflatoxin B1 in dried figs in Turkey by using a single laboratory-validated alkaline extraction method for ochratoxin A. J. Food Prot. 68, 1512–1515. Sewram, V., Shephard, G.S., van der Merwe, L., Jacobs, T.V., 2006. Mycotoxin contamination of dietary and medicinal wild plants in the Eastern Cape Province of South Africa. J. Agric. Food Chem. 54 (15), 5688–5693. Shaw, D., 1998. Risks or remedies? Safety aspects of herbal remedies in the UK. J. Roy. Soc. Med. 91, 294–296. Sheen, L.Y., Wu, C.C., Lii, C.K., Tsai, S.J., 2001. Effect of diallyl sulfide and diallyl disulfide, the active principles of garlic, on the aflatoxin B1-induced DNA damage in primary rat hepatocytes. Toxicol. Lett. 122, 45–52. Shim, W.B., Kim, K., Ofori, J.A., Chung, Y.C., Chung, D.H., 2012. Occurrence of aflatoxins in herbal medicine distributed in South Korea. J. Food Prot. 75 (11), 1991–1999. Singh, P., Srivastava, B., Kumar, A., Dubey, N.K., 2008. Fungal contamination of raw materials of some herbal drugs and recommendation of Cinnamomum camphora Oil as herbal fungitoxicant. Microb. Ecol. 56, 555–560. Sinha, R.C., Savard, M.E., 1996. Comparison of immunoassay and gas chromatography methods for the detection of the mycotoxin deoxynivalenol in grain samples. Can. J. Plant Pathol. 18, 233–236. Squire, R.A., 1989. Ranking animal carcinogens: a proposed regulatory approach. Science 214, 887–891. Szuets, P., Mesterhazy, A., Falkay, G.Y., Bartok, T., 1997. Early telarche symptoms in children and their relations to zearalenone contamination in foodstuffs. Cereal Res. Commun. 25, 429–436. Tan, Y., Kuang, Y., Zhao, R., Chen, B., Wu, J., 2011. Determination of T-2 and HT-2 toxins in traditional chinese medicine marketed in China by LC–ELSD after sample clean-up by two solid-phase extractions. Chromatographia 73 (3–4), 407–410. Tanaka, T., Hasegawa, A., Yamamoto, S., 1988. Worldwide contamination of cereals by the Fusarium mycotoxins nivalenol, deoxynivalenol, and zearalenone. 1. Survey of 19 countries. J. Agric. Food Chem. 36, 979–983. Tassaneeyakul, W., Razzazi-Fazeli, E., Porasuphatana, S., Bohm, J., 2004. Contamination of aflatoxins in herbal medicinal products in Thailand. Mycopathologia 158, 239–244. Tomaszewski, J., Mitursky, R., Semczuk, A., 1998. Tissue zearalenone concentration in normal, hyperplastic, and neoplastic human endometrium. Ginekol. Pol. 69, 363–366.

Torres, A.M., Reynoso, M.M., Rojo, F.G., Ramirez, M.L., Chulze, S.N., 2001. Fusarium species (section Liseola) and its mycotoxinas in maize harvested in northern Argentina. Food Addit. Contam. 18, 836–843. Tosun, H., Arslan, R., 2013. Determination of aflatoxin B1 levels in organic spices and herbs. Sci. World J.. http://dx.doi.org/10.1155/2013/874093, 874093. Tournas, V.H., Sapp, C., Trucksess, M.W., 2012. Occurrence of aflatoxins in milk thistle herbal supplements. Food Addit. Contam. 29 (6), 994–999. Trucksess, M., Weaver, C., Oles, C., D’Ovidio, K., Rader, J., 2006. Determination of Aflatoxins and Ochratoxin A in Ginseng and Other Botanical Roots by Immunoaffinity Column Cleanup and Liquid Chromatography with Fluorescence Detection. J. AOAC Int. 89 (3), 624–630. Trucksess, M., Weaver, C., Oles, C.J., Rump, L.V., White, K.D., Betz, J.M., Rader, J.I., 2007. Use of multitoxin immunoaffinity columns for determination of aflatoxins and ochratoxin A in ginseng and ginger. J. AOAC Int. 90 (4), 1042– 1049. Van der Merwe, K.J., Steyn, P.S., Fourie, L., 1965. Mycotoxins Part II. The constitution of ochratoxin A, B, C, metabolites of Aspergillus ochraceus Wilh.. J. Chem. Soc. 10, 7083–7088. Weaver, C.M., Trucksess, M.W., 2010. Determination of aflatoxins in botanical roots by a modification of AOAC official method SM 991.31: single-laboratory validation. J. AOAC Int. 93 (1), 184–189. WHO (World Health Organization), 1977. World Health Organization ResolutionPromotion and Development of Training and Research in Traditional Medicine, WHO document No.: 30–49. WHO (World Health Organization), 1998. Aflatoxins. In: Safety evaluation of certain food additives and contaminants. WHO Food Additive Series No. 40. Report of the 49th Meeting of the Joint FAO/WHO Expert Committee on Food Additives (JECFA). Geneva (Switzerland): WHO, pp. 359–468. Woo, J.H., Li, D., Wilsbach, K., Orita, H., Coulter, J., Tully, E., Kwon, T.K., Xu, S., Gabrielson, E., 2007. Coix seed extract, a commonly used treatment for cancer in China, inhibits NFkappaB and protein kinase C signaling. Cancer Biol. Ther. 6 (12), 2005–2011. Xie, T.T., Qiu, F., Yang, M.H., Qi, A.D., 2011. Simultaneous determination of fumonisins B1 and B2 in traditional Chinese medicines by high-performance liquid chromatography-tandem mass spectrometry. Yao Xue Xue Bao 46 (7), 822–827. Yang, M.H., Chen, J.M., Zhang, X.H., 2005. Immunoaffinity column clean-up and liquid chromatography with postcolumn derivatisation for analysis of aflatoxins in traditional Chinese medicine. Chromatographia 62, 499–504. Yang, J.Y., Zhang, Y.F., Wang, Y.Q., 2007. Toxic effects of zearalenone and azearalenol on the regulation of steroidogenesis and testosterone production in mouse Leydig cells. Toxicol. inVitro 21, 558–565. Yang, L., Wang, L., Pan, J., Xiang, L., Yang, M., Logrieco, A.F., 2010. Determination of ochratoxin A in traditional Chinese medicinal plants by HPLC-FLD. Food Addit. Contam. 27 (7), 989–997. Yue, Y., Zhang, X., Pan, J., Ou-Yang, Z., Wu, J., Yang, M., 2010. Determination of Deoxynivalenol in Medicinal Herbs and Related Products by GC–ECD and Confirmation by GC–MS. Chromatographia 71, 533–538. Zain, M.E., 2011. Impact of mycotoxins on humans and animals. J. Saudi. Chem. Soc. 15, 129–144. Zhang, X., Liu, H., Chen, J., 2005. Immunoaffinity column cleanup with liquid chromatography using post-column bromination for aflatoxins in medicinal herbs and plant extracts. J. Chromat. Sci. 43, 47–51. Zhang, X., Liu, W., Logrieco, A.F., Yang, M., Ou-yang, Z., Wang, X., Guo, Q., 2011. Determination of zearalenone in traditional Chinese medicinal plants and related products. Food Addit. Contam. 28 (7), 885–893. Zinedine, A., Mañes, J., 2009. Occurrence and legislation of mycotoxins in food and feed from Morocco. Food Control 20, 334–344.


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