Medical Mycolo gy 2000, 38, Supplement 1, 41 46

Mycotoxins and toxigenic fungi

J. I. PITT*, J. C. BASILICO , M. L. ABARCA & C. LO PEZ
*Fo od Science A ustralia, North Ryde , NSW , A ustralia; Depto de Ingeniera en A limentos, Universidad Nacional del
Lito ral, Santiago del Estero , A rgentina; Dept. de Patologia i Produccio A nimals, Universitat A uto`noma de Barcelona,
Spain; C ollege of Biochemistry, National University of Ro sario , A rgentina

Mycotoxins and the fungi that produce them are of increasing importance as causes
of human illness, but the diseases produced remain poorly understood at the clinical
level. This paper explores four aspects: the increase of interest in ochratoxin A,
factors affecting mycotoxin production, toxicology of the major mycotoxins, and the
identication of Penicillium species which cause food spoilage and are important in
indoor air.
Keywords mycotoxins, ochratoxin A, toxicology

Introduction OA has been reported in many plant products, espe-

Mycotoxins have become increasingly important in our
understanding of food safety and food poisoning. The
major problem with mycotoxins for the clinician is that
few produce overt signs of poisoning, and therefore myco-
toxicoses are very difcult to diagnose. This paper covers
several aspects of toxigenic fungi and mycotoxins of
interest to those engaged in medical mycology.
Ochratoxin A: an emerging mycotoxin
Ochratoxin A (OA) is a mycotoxin, which is receiving
increasing attention worldwide because of the hazard it
poses to animal and human health. Ochratoxins are
derivatives of isocumarin linked to L -b-phenylalanine and
are classied as pentaketides. OA has been demonstrated
to have nephrotoxic effects on all mammalian species. In
humans, this mycotoxin has been reported to be involved
in the epidemiology of Endemic Balkan Nephropathy, but
no clear relationship has been established [1]. Recently,
OA has also been linked to renal diseases in Tunisia and
Egypt [2,3]. OA is also known for its teratogenic, immuno-
suppressive and carcinogenic properties [4,5]. The Interna-
tional Agency of Research on Cancer has classied this
toxin as a possible human carcinogen [5].
Correspondence: Dr J. I. Pitt, Food Science Australia, P.O. Box 52,
North Ryde, N.S.W. 2113, Australia. Tel.: 612 9490 8525; fax:
612 9490 8499; e-mail: John.Pitt@foodscience.asc.csiro.au
cially in Europe, where the highest frequencies and levels
of OA contamination are found in cereals [4,6]. OA has
also recently been reported in wine and grape juice [7 9],
beer [10], green coffee beans and coffee [10,11].
Transfer of OA into meat from animals eating mouldy
feeds is also a serious problem. Pork and poultry meats
are regarded as the main animal sources of OA intake by
humans, although the OA levels in these products are low
compared with those in cereal products [5]. Recently, OA
has been also detected in milk [12]. Due to its occurrence
in such a wide range of food commodities, there is a
continuous human exposure to OA, especially in Europe.
The high incidence of OA in human blood serum [13,14]
and milk [15 17] in several countries reects a wide-
spread exposure of humans to OA. Its presence in human
blood has been suggested as an indicator for the indirect
assessment of exposure [6].
The World Health Organization has proposed a maxi-
mum limit for OA of 5 mg kg 1 in cereals. It can be
expected that a maximum level of 5 mg kg 1 for cereals
and cereal products will be established in world trade.
OA was originally isolated as a metabolite from Asper-
gillus ochraceus [18], and later from eight related species
[19,20]. However, many isolates of these species are not
toxigenic [1,21,22]. OA was also reported to be produced
by several Penicillium species; however, it is now accepted
that Penicillium errucosum is the only Penicillium species
producing OA [23].

2000 ISHAM
 42 Pitt et al.
It is generally believed that the occurrence of OA in
cereal and cereal products in northern Europe and North
America is due to P. errucosum [22,23]. However, little
evidence of serious contamination of tropical commodi-
ties by A. ochraceus or closely related species has been
found [22,23], so the source of OA contamination in
tropical foods remains unclear. Recently, the production
of OA by species in Aspergillus section Nigri (the black
Aspergilli) has received considerable attention [24 26]. In
particular, several studies have reported OA production
by A. carbonarius and many isolates have been shown to
be producers [27,28]. The taxonomy of Aspergillus section
Nigri is under revision [29 31], but the status of A.
carbonarius as the major producer of OA within this
group is not in doubt. This species is now considered to
be a major source of OA in tropical and subtropical
foods.
Factors affecting mycotoxin production
Fungal growth and mycotoxin production are the conse-
quence of an interaction among the fungus, the host and
the environment. The appropriate combination of these
factors determines the amount of colonization of the
substrate, and the type and amount of mycotoxin pro-
duced [32]. The synthesis of any particular mycotoxin
depends not only on the species but also on the strain
[33].
Many of the fungi capable of producing mycotoxins
are also frequent contaminants of food and agricultural
commodities. The mycotoxigenic fungi associated with
the human food chain belong mainly to three genera:
Aspergillus, Penicillium and Fusarium. While Fusarium
species are destructive plant pathogens producing myco-
toxins before or immediately after harvest, Penicillium
and Aspergillus species are more commonly found as
contaminants of commodities and foods during drying
and subsequent storage.
Mycotoxins cannot be produced unless fungal growth
occurs. However, the presence of mycotoxigenic fungi in
or on a food does not automatically mean the presence of
mycotoxins, but that a potential for mycotoxin produc-
tion exists. On the other hand, the absence of toxigenic
fungi does not guarantee that the commodity is free of
mycotoxins, as the toxins may persist long after the fungi
have lost viability [34].
The level of mycotoxin production is inuenced by the
nutrients available in the substrate. Environmental fac-
tors including temperature, water activity, gas atmo-
spheres and preservatives also affect mycotoxin
production [22,33].
A atoxins
Undoubtedly, the most important species of toxigenic
Aspergilli are those producing aatoxins, namely A.
aus and A. parasit icus. Both species grow at tempera-
tures ranging 10 12 C to 42 43 C, with an optimum
near 32 33 C, with aatoxins being produced between
12 and 40 C [35]. The optimum water activity (aw ) for
growth is near 099, with minima reported as 080
083 aw [36]. Aatoxins are produced in greater quantities
at higher water activities (098 099), with toxin produc-
tion ceasing at or near 085 aw . Although both species
grow over the pH range of just above 20 to ] 10,
aatoxin production for A. parasiticus has been reported
at between pH 30 and 80, with an optimum near pH 6
[35]. Reduction of available oxygen by modied atmo-
sphere packaging of foods in barrier lm or with oxygen
scavengers can inhibit aatoxin formation by A. aus
and A. parasiticus [37].
A number of nutritional factors inuence aatoxin
biosynthesis, including the presence of various carbohy-
drate and nitrogen sources, phosphates, lipoperoxides,
and trace metals in the growth medium [38]. How these
different factors act to regulate aatoxin biosynthesis is
unclear. Many of the effects may in fact be exerted
indirectly through interference with primary metabolism.
O chratoxin
P. errucosum is the principal producer of OA in temper-
ate climates. This is a cold climate fungus, growing
between 0 and 31 C, with and optimally at 20 C [39]. It
is a xerophile, capable of growing down to 080 aw [22]. It
grows over the pH range 21 10, with an optimum
between 60 and 70. OA is produced by this species over
the entire temperature range for growth, but not below
086 aw [39].
OA is also produced by A. ochraceus, A. carbonarius
and related species. A. ochraceus grows over the range
8 37 C, with OA produced over nearly all of this range.
The fungus has been reported to grow from 077 or
080 aw , but toxin production does not occur below about
083 aw [35]. A. carbonarius grows from about 10 40 C
but nothing is known about the conditions favouring
toxin production.
Fusarium toxins
Fusarium graminearum, a plant pathogen of gramineous
plants, especially wheat, is known to produce deoxyniva-
lenol, nivalenol and zearalenone [40]. It is the most
widely distributed toxigenic Fusarium species [41]. It
grows optimally at 24 26 C and grows at a minimum of
2000 ISHAM, Medical Mycology, 38, Suppl. 1, 4146

090 aw . The affect of pH on growth is temperature-de-
pendant, with minimum values of 24 at 30 C and 30 at
25 and 37 C. Toxin production largely mirrors growth
conditions [42].
F. moniliforme, which produces fumonisin B1 , grows
optimally between 225 275 C, with a minimum of 2 under the headings of absorption, transformation (activa-
5 C and a maximum of 32 37 C [22]. The minimum aw
for growth is 087, while fumonisin production has been
reported at as minimum of 092 aw [43].
Toxicological aspects of mycotoxins
Mycotoxins may be acutely toxic, carcinogenic, muta-
genic, teratogenic and:or immunosuppressive. Some sci-
entists are of the opinion that the single most effective
and benecial change that could be made in human diets
around the world would be the elimination of mycotoxins
[44].
Toxicological action depends on various factors: the
nature of the mycotoxin as well as the dose, the way of
entrance, the time of exposure and species susceptibility.
Susceptibility, in turn, is affected by different factors:
genetic and physiological factors such as age, hormones,
nutrition, intestinal microora, infections and parasitism
and environmental exposure, including weather condi-
tions and chemicals.
A atoxins
Aatoxin B1 is a type I human carcinogen [41] and the
most potent hepatocarcinogen known. Human fatalities
have also occurred from acute aatoxin poisoning: un-
seasonal rains in India and a scarcity of food caused the
consumption of heavily contaminated maize [45].
Studies of the molecular epidemiology of human can-
cer risks have added a new dimension to classical associa-
tive epidemiology by providing a direct link between
human cancer and carcinogen exposure. The p53 gene is
located on chromosome 17 and codes for a tumour-sup-
pressing protein, which contains 393 amino acids. In
human cancers, the p53 gene is frequently found to be
altered, and the p53 mutational spectrum reveals evidence
for a direct causal effect of ultraviolet radiation on skin
cancer, of tobacco smoke in lung cancer and of aatoxin
B1 in liver cancer.
Ecological studies as well as those on molecular epi-
demiology associate exposure to aatoxin with hepatocel-
lular carcinoma. Approximately 55% of the
hepatocarcinomas from areas where food is contami-
nated by aatoxin B1 contain an AGG AGT mutation
at codon 249 of the p53 tumour suppressor gene. This
mutation is also present in cultured human hepatocytes
2000 ISHAM, Medical Mycology, 38, Suppl. 1, 41 46
Mycotoxins and toxigenic fungi 43
exposed to aatoxin B1 . In contrast, less than 4% of
hepatocarcinomas from most developed countries, in
which exposure to aatoxin B1 is low, contain this
mutation.
The metabolic fate of the aatoxins may be considered
tion and detoxi cation), distribution and excretion. Ab-
sorption following oral exposure is complete, the
aatoxins are transported via the blood and not via the
lymphatic system. Transformation of aatoxin B1 results
in both activation and detoxi cation and may be consid-
ered to occur in two phases: (i) transformation of the
toxin to a selection of metabolites, and (ii) their conver-
sion to either water soluble conjugates or macromolecu-
lar adducts. The transformation process is modulated by
numerous factors including the genetic make-up of the
species, nutritional and health states, and exposure to
metabolic modiers in foodstuffs.
The major metabolites of aatoxin B1 include aatox-
ins B1 -8,9-epoxide and B1 -8,9-dihidrodiol; the aatoxins
B2 a , P1 , M 1 and Q; and the aatoxicols H1 and M 1 . In the
liver, aatoxin B1 may interact with both DNA and
protein to elicit carcinogenic and acutely toxic effects,
respectively. Initially, aatoxin B1 is converted by P450
cytochromes to the highly reactive aatoxin B1 -8,9-epox-
ide which, in turn, may be converted to aatoxin B1 -8,9-
dihydrodiol.
The carcinogenicity of aatoxin B1 arises from its
interaction with the guanine moiety of DNA to produce
the aatoxin-N7-guanine adduct, whereas the acute toxi-
city of aatoxin B1 is believed to stem from interaction
between the dihidroldiol and protein amino groups to
produce Schiff base adducts.
The aatoxin metabolites M 1 and P1 can also form
DNA adducts. Studies using guinea pig kidney micro-
somes have indicated that the two enzyme systems, cy-
tochrome P450 and prostaglandin H synthetase, are
equally active in the formation of DNA adducts.
Detoxication occurs via the conversion of aatoxin B1
to less active hydroxylated metabolites, such as the aa-
toxins M 1 , Q1 and P1 , and via the formation of the
glutathione (GSH) conjugate and glucoronides. The GSH
conjugate of aatoxin B1 -epoxide has been identied as
the major metabolite in the bile of rats. GSH conjugation
is mediated by cytosolic glutathione 5-transferases (GST)
and has an important reaction when determining the
susceptibility of species to the toxic effects of aatoxin.
This is illustrated by comparing the susceptibility of the
mouse and rat to tumour induction. Although the mouse
has a very high microsomal epoxidation activity, it is very
resistant to the carcinogenicity of aatoxin B1 , pre-
sumably because of its very high level of simultaneous
GST activity.
 44 Pitt et al.
After absorption from the intestine, aatoxin B1
rapidly enters the liver through the hepatic portal vein.
The toxin is heavily concentrated in the liver after oral,
intraperitoneal and intravenous administration. Much
less aatoxin accumulates in the kidney.
Excretion of aatoxin B1 occurs primarily through the
biliary pathway and to a lesser extent, the urinary path-
way, and by excretion into the milk of lactating animals
in the form of aatoxin M 1 .
O chratoxin A
OA causes renal toxicity, nephropathy and immunosup-
pression in several species, and is carcinogenic in experi-
mental animals. The nephrotoxic effects are related to the
fact that OA interacts with iron, forming a complex and
producing hydroxyl radicals that promote lipoperoxida-
tion. Renal damage is morphologically characterized by
atrophy of the proximal tubule, brosis and sclerosis. It
is functionally characterized by incapacity of the tubular
function, shown by a reduced ability to concentrate
urine.
No data are available on absorption, distribution,
metabolism and excretion of OA in humans. However, it
has been reported that in itro OA binds with extremely
high afnity to unidenti ed macromolecules in human
plasma and to plasma proteins.
The relative contribution of each excretory route for
OA varies with the species under study and the concen-
tration of specic OA metabolites in the urine.
T richothecenes
The consumption of foods contaminated with tri-
chothecenes is frequently associated with loss of appetite,
vomiting, lesions in the intestinal tract, immunosuppres-
sion, lethargy and ataxia. The immunosuppressive effect
is very dangerous since it is associated with agents that
cause tumours.
Various trichothecenes inhibit hepatic protein synthesis
to different degrees and cause an increase of tryptophan
in both blood and brain. Tryptophan is a precursor of
the neurotransmitter serotonin and the serotonergic neu-
rons are important mediators in such behaviours as ap-
petite, muscular coordination and sleep. Serotonin
synthesis in the brain seems to induce loss of appetite and
cause insomnia.
Zearalenone
Zearalenone is an oestrogen. Episodes of breast enlarge-
ment in young boys in Italy, and sexual precocity in
Puerto Rico have been reported, both of which may have
been caused by zearalenone in maize. This toxin may
therefore have a role in hormonal balance and mammary
cancer in regions with high zearalenone ingestion.
Fumonisins
Exposure to fumonisin B1 in maize is the cause of
leukoencephalomalacia in horses, a disease known for a
long time in many countries. Fumonisin B1 also causes
pulmonary oedema in pigs and it is also toxic to the
central nervous system, liver, pancreas, kidney and lung
in a number of animal species.
A correlation has been found between fumonisin in-
take and rates of human oesophageal cancer in Transkei,
South Africa and in parts of China [46,47]. Fumonisins
are believed to be tumour promoters and have been
classied as class 2B carcinogens [41]. Fumonisins alter
sphingolipid metabolism and disrupt the barrier function
of endothelial cells in culture. They inhibit synthetase
ceramide, blocking the synthesis of sphingolipids and
causing accumulation of sphingosine. This alters cellular
regulation and communication, causing neurological dis-
eases in humans.
Identi cation of Penicillium species as food
contaminants
Penicillium species are very common in foodstuffs. Many
species cause spoilage, make mycotoxins, or cause delete-
rious biochemical changes to foods. These effects are
almost always species specic, so identication of Penicil-
lium to species level is very important in food preserva-
tion and safety. Many of these species also occur in
indoor air, and can be allergenic, and here again accurate
identication is important.
Specic associations
Some Penicillium species have specic associations with
foods, enabling presumptive identication after isolation.
A collection of such species can be very helpful in devel-
oping expertise in identication. Species of this kind
include P. expansum, the apple rot fungus, P. digitat um,
which causes green mould on oranges and other citrus
fruits, and P. italicum, cause of a similar blue mould. P.
roqueforti can be isolated from any type of blue cheese,
and P. camemberti from mould-ripened cheeses such as
camembert and brie. Spoiled cheese is a rich source of
Penicillium species: P. commune is the most common. P.
glabrum is a frequent contaminant of fruit juices. P.
oxalicum and P. funiculosum are usually associated with
2000 ISHAM, Medical Mycology, 38, Suppl. 1, 4146

maize kernels. P. citrinum and P. chrysogenum are of
universal occurrence, and can be isolated from almost
any substrate. Both species are readily recognized.
Isolation
To isolate Penicillium species from foods, indoor air or
indeed most other substrates, the use of Dichloran Rose
Bengal chloramphenicol (DRBC) agar or Dichloran 18%
glycerol (DG18) agar is recommended [22]. Incubation of
these media at 25 C for 4 5 days will usually result in
recognizable Penicillium colonies. Most species grow
slowly and produce colonies recognizable by blue-green
sporulation. A few species sporulate weakly under these
conditions, and microscopic examination may be needed
to enable recognition to genus level.
Identication
Identication of Penicillium species is usually based on
the methods of Pitt & Hocking [22] and Pitt [48,49]. This
system requires the use of Czapek yeast extract agar
(CYA), malt extract agar and preferably glycerol nitrate
agar [22,48,49]. Cultures are inoculated according to a
standard regimen and incubated for 7 days, with three
Petri dishes at 25 C and one each at 5 and 37 C. In
addition, neutral creatine sucrose (CSN) agar is used as
an aid in the identication of species in Penicillium sub-
genus Penicillium [22,49].
The main characteristics used for identi cation are
penicillin type on CYA and:or MEA, colony diameter on
the standard media and microscopic characters. Less
emphasis is placed on colony colour and texture.
Penicillium species are not easy to identify by the
beginner. The major requirement for accurate identica-
tion is practice; therefore, collecting a set of standard
cultures as suggested above is a very helpful aid. With
them it is possible to assess the efcacy of the media
being used, and to determine if colony diameters are in
agreement with those provided in the text being used. If
they are not, changes in media ingredients, checks of
incubator temperatures, or simply compensation for dif-
ferences observed when the keys are used are all
important.
Penicillium characteristics are all variable, so it is im-
possible for keys to be constructed which work at all
times. It is important, therefore, to always check descrip-
tions to ensure accurate results. If necessary, the keys
should be reworked until an accurate t is obtained.
PENNAME, an independent system, which uses a com-
puter based synoptic key to arrive at identications, can
be a very useful aid [50].
2000 ISHAM, Medical Mycology, 38, Suppl. 1, 41 46
Mycotoxins and toxigenic fungi 45
Contributors
The contributors to this symposium were: M. Lourdes
Abarea, Ochratoxin A: an emerging mycotoxin; J. C.
Basi lico, Factors that inuence mycotoxin synthesis; C.
Lopez, Toxicological aspects of mycotoxins ; J. Pitt, Iden-
tication of Penicillium species as food contaminants. The
chairpersons were J. I. Pitt and J. C. Basi lico.
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