A Review of Recent Advances in Understanding Ochratoxicosis'l2 Ronald R. Marquardt and Andrzej A. Frohlich Department of Animal Science, University of Manitoba, Winnipeg, R3T 2N2 Canada
its long half-life in animals. Ochratoxin A is by hydrolyzed to its nontoxic alpha form (01x1 microorganisms in the rumen, cecum, and large intestine. The toxin is excreted primarily in the urine as O a and to a lesser degree as OA; smaller amounts of OA and O a are generally excreted in the feces. Three distinct mechanisms of OA toxicity have been proposed; other toxic effects of OA seem to be secondary in nature. Several different strategies can be employed for controlling or neutralizing the effect of OA, including the use of proper storage conditions, the use of specific adsorbents to reduce absorption of OA, and the feeding OA-contaminated feedstuffs to ruminants. Antioxidants such as ascorbic acid have been shown to reduce the toxic effects of OA in laying hens. In summary, OA contamination of cereal food and feed may occur, given appropriate conditions. Implementation of suitable procedures may eliminate or minimize this potentially serious problem.
Key Words: Ochratoxins, Toxicology, Reviews, Metabolism, Detoxification
J. Anim. Sci. 1992. 70:3968-3988
Introduction Ochratoxin is a toxic compound that is commonly produced by two species of fungi, Penicillium verrucoswn Dierckx (Frisvad and Samson, 1991) and Aspergillus ochruceus Wilhelm (De Scott, 1985; Frisvad and Samson, 1991). The latter fungal species is now referred to as A. ulutaceus Berkeley
'Presented at a symposium titled: "Current Perspectives on Mycotoxins in Animal Feeds" at the ASAS 83rd Annu. Mtg., Laramie, WY. 2Financial support from NSERC and the Western Grains Research Foundation is gratefully acknowledged. Received January 21, 1992. Accepted July 28, 1992.
et Curtis (Kozakiewicz, 1989). The primary toxin was identified as ochratoxin A (OA); its less toxic dechloro analog is ochratoxin B (OB)(van der Merwe et al., 1965a,b). Several other forms of ochratoxin also occur. Ochratoxin in recent years has received considerable attention because not only can it seriously affect animal performance and well-being, but it may also have deleterious effects on humans. Of greatest concern in humans is its implicated role in a n irreversible and fatal kidney disease referred to as Balkan endemic nephropathy and its potent carcinogenic effects. This review discusses current information on the production of OA by certain species of fungi; naturally occurring ochratoxicosis; ochratoxicosis in pigs, poultry, ruminants, and laboratory animals; the acute and chronic effects of the toxin;
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ABSTRACT8 Ochratoxin A ( O N is a toxin that contains an isocoumarin moiety linked by a peptide bond to phenylalanine. It is produced by certain Penicillium (mainly P. verrucosum) and Aspergillus (mainly A. ulutuceusl species of storage fungi. Total amounts of OA and other related toxins produced by these fungi are influenced by many factors. Several forms of OA have been discovered, some of which are highly toxic, whereas others have lower toxicity. Ochratoxin A has been detected in foods, feeds, animal tissues, and human blood in both Europe and North America. It has been implicated in the fatal human disease Balkan endemic nephropathy, has been shown to be a powerful carcinogen in rodents, and produces many other adverse effects in animals. It is absorbed passively throughout the gastrointestinal tract and in an active manner in the kidney. It is subjected to intestinal secretion and reabsorption via enterohepatic recycling. Binding of OA in the blood to the albumin fraction and recycling in the bile and kidney contributes to
A REVIEW OF OCHRATOXICOSIS
19901.
Chemistry of Ochratoxins and General Toxicity Ochratoxin A contains 7-carboxy-5-chloro-8hydroxy9,4-dihydro-3R-methylisocoumarin (Oal that is linked through the 7-carboxy group to L-pphenylalanine by an amide bond. Several forms of ochratoxin occur (Table 1, Figure 11, each of varying toxicity. In addition to OA, OB also exists in both the methyl and ethyl ester forms (Chu, 1974). Hydroxylated forms of OA have been identified, including (4RI-OH-OA, (4S)-OH-OA, and 10-OH-OAWormer et al., 19831. Several analogs of OA have been prepared by substitution of phenylalanine with other amino acids (Creppy et al., 1983a1. The tyrosine, valine, serine, and alanine analogs are most toxic, the methionine, tryptophan, and glutamic acid analogs have intermediate toxic effects, and the glutamate and proline analogs have low toxicity. Recently, Hadidane et al. (19911 have reported that the serine, hydroxyproline, and lysine analogs also occur naturally. Studies by Creppy et al. (1990) have also demonstrated that OA can be hydroxylated by phenylalanine hydroxylase to form the tyrosine analog of OA.
0
OH
0
Ochratoxin A has two ionizable groups, the carboxyl group from phenylalanine and the 8-hydroxyl group, both of which can exist in the ionized or non-ionized form under physiological conditions. The dissociation constant (pKa1 of the 8-hydroxyl group is influenced by the structure of the OA; the pKa values are 7.05 to 7.10 for OA and ochratoxin C (OCI, 8.0 for OB, and 11.O for Oa. Chu (19741 demonstrated that the 8-hydroxyl group must exist in the dissociated form for ochratoxin intoxication. The role of the carboxyl group in OA toxicity has not been reported. The chemical and physical properties have been reviewed in greater detail by Chu (19741, Cole and Cox (19811, and Steyn (19841.
Ochratoxin-Producing Molds The most important filamentous fungal genera invading cereal grains in storage are a large number of Penicillium and Aspergillus, several of which produce OA (Frisvad and Samson, 1991). These fungi have been referred to as storage fungi. Among the Aspergillus species, A. alutaceus (A. ochraceus),A. ostianus, A. quercins (A. melleusl, and A . sulphureus (A. fresenii) produce OA. A. ochraceus is the only important cereal-borne producer of this toxin (Frisvad and Samson, 19911. Among the Pennicillium species, P. verrucosurn is the only known and confirmed producer of OA (Pitt, 1987, 1988; Frisvad and Filtenborg, 1989; Frisvad and Samson, 1991). Two different strains of P. verrucosum have been identified, P. verrucosum chemotype I, which produces OA, verrucolon, and citrinin, and P. verrucosum chemotype 11, which produces only OA and verrucolon. Cereal-borne P. verrucosum (chemotype I11 has only been found in Denmark, Sweden, Norway, United Kingdom, Canada, and the United States (Frisvad and Filtenborg, 1989; Frisvad and Samson, 1991). The reported production of OA by numerous other species of Penicillium and Aspergillus has been attributed to the difficulty associated with the correct identification of fungal species (Frisvad, 1989; Pitt and Samson, 1990; Samson and Frisvad, 1991). These problems have been overcome by the introduction of new taxonomical techniques (Pitt and Samson, 19901.
Factors That Influence Ochratoxin A Production
Figure 1. General strucutre of ochratoxin. See Table 1 for structure of the different R groups.
The amount of OA produced by any given species is influenced by many factors, including water activity (awl,temperature, type of substrate, presence of competitive microflora, strain of fungi, and integrity of the seed. The minimum a, values
Downloaded from https://academic.oup.com/jas/article-abstract/70/12/3968/4632088 by Iowa State University user on 11 January 2019
factors affecting absorption, distribution, biotransformations, and excretic,? of OA and its metabolites; its biochemical mechanism of action; the degree to which humans are exposed to the toxin; and means by which the toxic effects of OA can be reduced. Several reviews have been published on different aspects of OA (Chu, 1974; Cole and Cox, 1981; Roschenthaler et al., 1984; Steyn, 1984; Schaeffer and Hamilton, 1986; Burns and Dwivedi, 1988; Dwivedi and Burns, 1988; Kuiper-Goodman, 1990; Marquardt et al., 1990; Pestka and Bondy,
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MARQUARDT AND FROHLICH
Table 1. Naturally occurring forms of the ochratoxinsa Common name
R2
R3
R4
R5
OA OB
Phenylalanyl Phenylalanyl Phenylalanyl, ethyl ester Phenylalanyl, methyl ester Phenylalanyl, methyl ester Phenylalanyl, ethyl ester OH OH Phenylalanyl Phenylalanyl Phenylalanyl Tyrosine Serine Hydroxyproline Lysine
c1
H H H H H H H H H OH H H H H H
H H H H H H H H OH H H
H H H H H H H H H H OH H H H H
oc O C X OP
OH-OA OH-OA OH-OA
H c1
c1
H H c1 H
c1 c1 c1 c1 c1
c1 c1
H H H H
~~
&The location of the R groups on the ochratoxin molecule are outlined in Figure 1. R 1 through 5 refers to that group bound to carbons 9, 5, 4, 4, and the number 3 methyl carbon, respectively, of ochratoxin.
for OA production by A. altutaceus and P. verrucosum were in the range of from .83 to .90. At 24"C, the optimum a, values were from .95 to .99 (Northolt et al., 1979).At optimum h, the temperature range for OA production by A. alutaceus was 12 to W'C, whereas that for P. verrucosum was 4 to 31OC. These data correspond with observations on OA contamination in stored grain. The more psycophilic Penicillia, specifically P. verrucosum, is the major OA producer in cereals in the colder climatic zones, such as Scandinavia and Canada (Krogh, 1987). In contrast, OA production in crops in the warmer climatic zones, such as Yugoslavia and Australia, is primarily by strains of A. alutaceus (Krogh, 1987). The substrate on which Penicillium and Aspergillus species of fungi are grown greatly influences OA production (Filtenborg et al., 1990; Pitt and Samson, 1990). An in vitro study (Madhyastha et al., 1990) followed the time course production of OA, OB, and citrinin by two species of fungi, A. alutaceus and P. verrucosum, when grown on two grain crops (wheat and corn) and three oilseed crops (soybeans, peanuts, and rapeseed). The results as shown in Table 2 demonstrated that the oilseeds (peanuts and soybeans) supported a much higher production of OA and OB by A. alutaceus than did the grain crops (wheat and corn), whereas the two grains were a much better substrate for the production of OA and citrinin by P. verrucosum than the oilseed crops. Interestingly, OB was only produced by A. alutaceus when grown on the oilseed crops but not on the cereal crops. Also, there did not seem to be a close association between total amount of fungal mass and amount of mycotoxin produced. The presence of competing microflora on a cereal substrate also affects the production of OA
by A. alutaceus (Chelack et al., 1991al. These authors demonstrated that the production of OA by A. alutaceus on sterilized barley was much greater than its production of OA on unsterilized barley and that OA production by this fungus was greatly suppressed by the reintroduction of non OA-producing flora that had been isolated from the barley. It should therefore be possible to reduce the production of OA by A. alutaceus, and possibly that by P. verrucosum, by innoculation of high-moisture grain with a strain of bacteria or
Table 2. Influence of fungal species and substrate on ochratoxin A (OA), ochratoxin B (OB), and citrinin production (30-day incubation period) by two storage fungia ~~
Species and substrate
Aspergillus alutaceus Grains Corn Wheat 0i1seeds Soybeans Peanuts
OA, W g (PPd
OBb, Wg (PPd
Citrinin, Fungal W g massc, mg/g (PPd
74 72
0
0
2.5
0
0
8.3
243
388
342
132
0 0
25.8
7.8
Penicillium verrucosum Grains Corn
Wheat Oilseeds Soybeans Peanuts
0 0
128
3.6
98
102
10.1
7 18
0 0
0
8.4 8.4
21d
0
*Data from Madhyastha et al. (1990). bOB, dechloro form, low toxicity. CFungal mass as determined from glucosamine concentration. dLow because of low amount of fungal mass.
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Ochratoxin A Ochratoxin B Ochratoxin C Ochratoxin A methyl ester Ochratoxin B methyl ester Ochratoxin B ethyl ester Ochratoxin a Ochratoxin p 4R-Hydroxyochratoxin A 4s-Hydroxyochratoxin A 10-Hydroxyochratoxin A Ochratoxin A, tyrosine analog Ochratoxin A, serine analog Ochratoxin A, hydroxyproline analog Ochratoxin A, lysine analog
R'
Abbreviation
A REVIEW OF OCHRATOXICOSIS
Contamination of Food and Feed by Ochratoxins Plant Products. Ochratoxin A has been shown to occur in various grains, cereals, and other plant products, animal feeds, meats, and human tissues in countries throughout the world (Bauer and Gareis, 1987; Bacha et al., 1988; Bauer et al., 1988; Marquardt et al., 1988; Tsubouchi et al., 1988; Jelinek et al., 1989; Frank, 1991; Hald, 19911. The natural occurrence of OA in cereals, particularly barley, together with the wide distribution in the environment of OA-producing fungi has caused concern about the transmission of OA into the human food chain. Krogh (19871 summarized studies on the natural occurrence of OA in food and feeds from 13 countries, including Canada and the United States, up to 1983. The percentage of the food or feed that was contaminated ranged from 1 to 30%. In Canada and the United States the range was from 1 to 14.2%. The mean concentration of OA in all reported surveys up to 1979 was 1,035 pg/kg, with 83% of samples containing
its long half-life in animals. Ochratoxin A is by hydrolyzed to its nontoxic alpha form (01x1 microorganisms in the rumen, cecum, and large intestine. The toxin is excreted primarily in the urine as O a and to a lesser degree as OA; smaller amounts of OA and O a are generally excreted in the feces. Three distinct mechanisms of OA toxicity have been proposed; other toxic effects of OA seem to be secondary in nature. Several different strategies can be employed for controlling or neutralizing the effect of OA, including the use of proper storage conditions, the use of specific adsorbents to reduce absorption of OA, and the feeding OA-contaminated feedstuffs to ruminants. Antioxidants such as ascorbic acid have been shown to reduce the toxic effects of OA in laying hens. In summary, OA contamination of cereal food and feed may occur, given appropriate conditions. Implementation of suitable procedures may eliminate or minimize this potentially serious problem.
Key Words: Ochratoxins, Toxicology, Reviews, Metabolism, Detoxification
J. Anim. Sci. 1992. 70:3968-3988
Introduction Ochratoxin is a toxic compound that is commonly produced by two species of fungi, Penicillium verrucoswn Dierckx (Frisvad and Samson, 1991) and Aspergillus ochruceus Wilhelm (De Scott, 1985; Frisvad and Samson, 1991). The latter fungal species is now referred to as A. ulutaceus Berkeley
'Presented at a symposium titled: "Current Perspectives on Mycotoxins in Animal Feeds" at the ASAS 83rd Annu. Mtg., Laramie, WY. 2Financial support from NSERC and the Western Grains Research Foundation is gratefully acknowledged. Received January 21, 1992. Accepted July 28, 1992.
et Curtis (Kozakiewicz, 1989). The primary toxin was identified as ochratoxin A (OA); its less toxic dechloro analog is ochratoxin B (OB)(van der Merwe et al., 1965a,b). Several other forms of ochratoxin also occur. Ochratoxin in recent years has received considerable attention because not only can it seriously affect animal performance and well-being, but it may also have deleterious effects on humans. Of greatest concern in humans is its implicated role in a n irreversible and fatal kidney disease referred to as Balkan endemic nephropathy and its potent carcinogenic effects. This review discusses current information on the production of OA by certain species of fungi; naturally occurring ochratoxicosis; ochratoxicosis in pigs, poultry, ruminants, and laboratory animals; the acute and chronic effects of the toxin;
3968
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ABSTRACT8 Ochratoxin A ( O N is a toxin that contains an isocoumarin moiety linked by a peptide bond to phenylalanine. It is produced by certain Penicillium (mainly P. verrucosum) and Aspergillus (mainly A. ulutuceusl species of storage fungi. Total amounts of OA and other related toxins produced by these fungi are influenced by many factors. Several forms of OA have been discovered, some of which are highly toxic, whereas others have lower toxicity. Ochratoxin A has been detected in foods, feeds, animal tissues, and human blood in both Europe and North America. It has been implicated in the fatal human disease Balkan endemic nephropathy, has been shown to be a powerful carcinogen in rodents, and produces many other adverse effects in animals. It is absorbed passively throughout the gastrointestinal tract and in an active manner in the kidney. It is subjected to intestinal secretion and reabsorption via enterohepatic recycling. Binding of OA in the blood to the albumin fraction and recycling in the bile and kidney contributes to
A REVIEW OF OCHRATOXICOSIS
19901.
Chemistry of Ochratoxins and General Toxicity Ochratoxin A contains 7-carboxy-5-chloro-8hydroxy9,4-dihydro-3R-methylisocoumarin (Oal that is linked through the 7-carboxy group to L-pphenylalanine by an amide bond. Several forms of ochratoxin occur (Table 1, Figure 11, each of varying toxicity. In addition to OA, OB also exists in both the methyl and ethyl ester forms (Chu, 1974). Hydroxylated forms of OA have been identified, including (4RI-OH-OA, (4S)-OH-OA, and 10-OH-OAWormer et al., 19831. Several analogs of OA have been prepared by substitution of phenylalanine with other amino acids (Creppy et al., 1983a1. The tyrosine, valine, serine, and alanine analogs are most toxic, the methionine, tryptophan, and glutamic acid analogs have intermediate toxic effects, and the glutamate and proline analogs have low toxicity. Recently, Hadidane et al. (19911 have reported that the serine, hydroxyproline, and lysine analogs also occur naturally. Studies by Creppy et al. (1990) have also demonstrated that OA can be hydroxylated by phenylalanine hydroxylase to form the tyrosine analog of OA.
0
OH
0
Ochratoxin A has two ionizable groups, the carboxyl group from phenylalanine and the 8-hydroxyl group, both of which can exist in the ionized or non-ionized form under physiological conditions. The dissociation constant (pKa1 of the 8-hydroxyl group is influenced by the structure of the OA; the pKa values are 7.05 to 7.10 for OA and ochratoxin C (OCI, 8.0 for OB, and 11.O for Oa. Chu (19741 demonstrated that the 8-hydroxyl group must exist in the dissociated form for ochratoxin intoxication. The role of the carboxyl group in OA toxicity has not been reported. The chemical and physical properties have been reviewed in greater detail by Chu (19741, Cole and Cox (19811, and Steyn (19841.
Ochratoxin-Producing Molds The most important filamentous fungal genera invading cereal grains in storage are a large number of Penicillium and Aspergillus, several of which produce OA (Frisvad and Samson, 1991). These fungi have been referred to as storage fungi. Among the Aspergillus species, A. alutaceus (A. ochraceus),A. ostianus, A. quercins (A. melleusl, and A . sulphureus (A. fresenii) produce OA. A. ochraceus is the only important cereal-borne producer of this toxin (Frisvad and Samson, 19911. Among the Pennicillium species, P. verrucosurn is the only known and confirmed producer of OA (Pitt, 1987, 1988; Frisvad and Filtenborg, 1989; Frisvad and Samson, 1991). Two different strains of P. verrucosum have been identified, P. verrucosum chemotype I, which produces OA, verrucolon, and citrinin, and P. verrucosum chemotype 11, which produces only OA and verrucolon. Cereal-borne P. verrucosum (chemotype I11 has only been found in Denmark, Sweden, Norway, United Kingdom, Canada, and the United States (Frisvad and Filtenborg, 1989; Frisvad and Samson, 1991). The reported production of OA by numerous other species of Penicillium and Aspergillus has been attributed to the difficulty associated with the correct identification of fungal species (Frisvad, 1989; Pitt and Samson, 1990; Samson and Frisvad, 1991). These problems have been overcome by the introduction of new taxonomical techniques (Pitt and Samson, 19901.
Factors That Influence Ochratoxin A Production
Figure 1. General strucutre of ochratoxin. See Table 1 for structure of the different R groups.
The amount of OA produced by any given species is influenced by many factors, including water activity (awl,temperature, type of substrate, presence of competitive microflora, strain of fungi, and integrity of the seed. The minimum a, values
Downloaded from https://academic.oup.com/jas/article-abstract/70/12/3968/4632088 by Iowa State University user on 11 January 2019
factors affecting absorption, distribution, biotransformations, and excretic,? of OA and its metabolites; its biochemical mechanism of action; the degree to which humans are exposed to the toxin; and means by which the toxic effects of OA can be reduced. Several reviews have been published on different aspects of OA (Chu, 1974; Cole and Cox, 1981; Roschenthaler et al., 1984; Steyn, 1984; Schaeffer and Hamilton, 1986; Burns and Dwivedi, 1988; Dwivedi and Burns, 1988; Kuiper-Goodman, 1990; Marquardt et al., 1990; Pestka and Bondy,
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MARQUARDT AND FROHLICH
Table 1. Naturally occurring forms of the ochratoxinsa Common name
R2
R3
R4
R5
OA OB
Phenylalanyl Phenylalanyl Phenylalanyl, ethyl ester Phenylalanyl, methyl ester Phenylalanyl, methyl ester Phenylalanyl, ethyl ester OH OH Phenylalanyl Phenylalanyl Phenylalanyl Tyrosine Serine Hydroxyproline Lysine
c1
H H H H H H H H H OH H H H H H
H H H H H H H H OH H H
H H H H H H H H H H OH H H H H
oc O C X OP
OH-OA OH-OA OH-OA
H c1
c1
H H c1 H
c1 c1 c1 c1 c1
c1 c1
H H H H
~~
&The location of the R groups on the ochratoxin molecule are outlined in Figure 1. R 1 through 5 refers to that group bound to carbons 9, 5, 4, 4, and the number 3 methyl carbon, respectively, of ochratoxin.
for OA production by A. altutaceus and P. verrucosum were in the range of from .83 to .90. At 24"C, the optimum a, values were from .95 to .99 (Northolt et al., 1979).At optimum h, the temperature range for OA production by A. alutaceus was 12 to W'C, whereas that for P. verrucosum was 4 to 31OC. These data correspond with observations on OA contamination in stored grain. The more psycophilic Penicillia, specifically P. verrucosum, is the major OA producer in cereals in the colder climatic zones, such as Scandinavia and Canada (Krogh, 1987). In contrast, OA production in crops in the warmer climatic zones, such as Yugoslavia and Australia, is primarily by strains of A. alutaceus (Krogh, 1987). The substrate on which Penicillium and Aspergillus species of fungi are grown greatly influences OA production (Filtenborg et al., 1990; Pitt and Samson, 1990). An in vitro study (Madhyastha et al., 1990) followed the time course production of OA, OB, and citrinin by two species of fungi, A. alutaceus and P. verrucosum, when grown on two grain crops (wheat and corn) and three oilseed crops (soybeans, peanuts, and rapeseed). The results as shown in Table 2 demonstrated that the oilseeds (peanuts and soybeans) supported a much higher production of OA and OB by A. alutaceus than did the grain crops (wheat and corn), whereas the two grains were a much better substrate for the production of OA and citrinin by P. verrucosum than the oilseed crops. Interestingly, OB was only produced by A. alutaceus when grown on the oilseed crops but not on the cereal crops. Also, there did not seem to be a close association between total amount of fungal mass and amount of mycotoxin produced. The presence of competing microflora on a cereal substrate also affects the production of OA
by A. alutaceus (Chelack et al., 1991al. These authors demonstrated that the production of OA by A. alutaceus on sterilized barley was much greater than its production of OA on unsterilized barley and that OA production by this fungus was greatly suppressed by the reintroduction of non OA-producing flora that had been isolated from the barley. It should therefore be possible to reduce the production of OA by A. alutaceus, and possibly that by P. verrucosum, by innoculation of high-moisture grain with a strain of bacteria or
Table 2. Influence of fungal species and substrate on ochratoxin A (OA), ochratoxin B (OB), and citrinin production (30-day incubation period) by two storage fungia ~~
Species and substrate
Aspergillus alutaceus Grains Corn Wheat 0i1seeds Soybeans Peanuts
OA, W g (PPd
OBb, Wg (PPd
Citrinin, Fungal W g massc, mg/g (PPd
74 72
0
0
2.5
0
0
8.3
243
388
342
132
0 0
25.8
7.8
Penicillium verrucosum Grains Corn
Wheat Oilseeds Soybeans Peanuts
0 0
128
3.6
98
102
10.1
7 18
0 0
0
8.4 8.4
21d
0
*Data from Madhyastha et al. (1990). bOB, dechloro form, low toxicity. CFungal mass as determined from glucosamine concentration. dLow because of low amount of fungal mass.
Downloaded from https://academic.oup.com/jas/article-abstract/70/12/3968/4632088 by Iowa State University user on 11 January 2019
Ochratoxin A Ochratoxin B Ochratoxin C Ochratoxin A methyl ester Ochratoxin B methyl ester Ochratoxin B ethyl ester Ochratoxin a Ochratoxin p 4R-Hydroxyochratoxin A 4s-Hydroxyochratoxin A 10-Hydroxyochratoxin A Ochratoxin A, tyrosine analog Ochratoxin A, serine analog Ochratoxin A, hydroxyproline analog Ochratoxin A, lysine analog
R'
Abbreviation
A REVIEW OF OCHRATOXICOSIS
Contamination of Food and Feed by Ochratoxins Plant Products. Ochratoxin A has been shown to occur in various grains, cereals, and other plant products, animal feeds, meats, and human tissues in countries throughout the world (Bauer and Gareis, 1987; Bacha et al., 1988; Bauer et al., 1988; Marquardt et al., 1988; Tsubouchi et al., 1988; Jelinek et al., 1989; Frank, 1991; Hald, 19911. The natural occurrence of OA in cereals, particularly barley, together with the wide distribution in the environment of OA-producing fungi has caused concern about the transmission of OA into the human food chain. Krogh (19871 summarized studies on the natural occurrence of OA in food and feeds from 13 countries, including Canada and the United States, up to 1983. The percentage of the food or feed that was contaminated ranged from 1 to 30%. In Canada and the United States the range was from 1 to 14.2%. The mean concentration of OA in all reported surveys up to 1979 was 1,035 pg/kg, with 83% of samples containing
