Transcript Mycotoxins

Mycotoxins
1
Introduction
• Mycotoxin is a convenient generic term describing the toxic
secondary metabolites produced by fungi.
Mycotoxins are secondary metabolites of fungi that are
recognized as toxic to other life forms.
“Myco” means fungal (mold) and “toxin” represents poison.
• They encompass a considerable variety of low molecular weight
compounds with diverse chemical structures and biological
activities.
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Secondary metabolite: A compound that is not necessary for
growth or maintenance of cellular functions but is synthesized,
generally, for the protection of a cell or micro-organism, during the
stationary phase of the growth cycle. Many are used in foods,
pharmaceuticals, and other industrial applications.)
Introduction
Some mycotoxins could also be toxic to plants or other
microorganisms; but these compounds are not classified as
antibiotics of fungal origin.
Like most microbial secondary metabolites, the benefit of
mycotoxins for the fungi themselves is still not clearly defined.
Due to their diverse chemical structures, mycotoxins may exhibit a
number of biological effects, including both acute and chronic
toxic effects as well as carcinogenic, mutagenic, genotoxic, and
immunotoxic effects.
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Introduction
• The interaction of mycotoxins with cellular macromolecules plays
a dominant role in their toxic actions.
•
Recent studies on the effect of mycotoxins on apoptosis have
further revealed their mode of action at the cellular level.
• In considering the effects of mycotoxins on animals, it is important
to distinguish between “mycotoxicosis” and “mycosis.”:
• Mycotoxicosis is used to describe the action of mycotoxin(s) and is
frequently mediated through a number of organs, notably the liver,
kidney, lungs, and the nervous, endocrine, and immune systems.
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Introduction
• Mycosis” refers to a generalized invasion of living tissue(s) by
growing fungi.
1. Fungal growth
a. Field fungi : grow under conditions occurring prior to
harvest. (Fusarium)
b. Storage fungi : do not invade intact grain prior to
harvest. (Aspergillus & Penicillium)
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Introduction
2. Characteristics of mycotoxin induced disease
a.
Not transmitted among animals
b. Pharmaceutical treatment does not alter the course of disease
c. Mycotoxicosis most often presents as a uncertain, sub-acute or
chronic condition
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Introduction
3. Treatment of mycotoxin - induced disease
a. For most mycotoxins, there is no specific treatment or antidote
b. Supplement with vitamins & selenium may be helpful, and
provision of adequate high-quality protein
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Introduction
4. Prevention of mycotoxin-induced disease
a. Avoiding
b. Diluting
c. Cleaning
d. Drying
e. Adding (organic acids will prevent mold growth)
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I- Production of mycotoxins by toxogenic fungi
Invasion by fungi and production of mycotoxins in commodities can
occur under favorable conditions in the field, at harvest, and during
processing, transportation and storage
Fungi that are frequently found in the field include:
Aspergilus flavus, Alternaria longipes, Alternaria alternata,
Claviceps purpura, Fusarium verticillioides (previously called
moniliforme), Fusarium graminearum, and a number of other
Fusarium spp.
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Species most likely introduced at harvest include:
•
Fusarium sporotrichioides, Stachybotrys atra, Cladosporium
sp., Myrothecium verrucaria, Trichothecium roseum, as well
as Alternaria alternata.
Species most likely found in the storage are mostly from
genus Penicillia and include:
•
Penicillium citrinum, P. cyclopium, P. citreoviride, P.
islandicum, P. rubrum, P. viridicatum, P. urticae, P.
verruculosum, P. palitans, P. puberulum, P. expansum, and P.
roqueforti.
All of which are capable of producing mycotoxins in grains and
foods.
• Other toxicogenic storage fungi are:
Aspergillus parasiticus, A. flavus, A. versicolor, A. ochraceus,
A. clavatus, A. fumigatus, A. rubrum, A. chevallieri,
Fusarium verticillioides, F. tricinctum, F. nivale, and several
other Fusarium spp.
• It is apparent, most of the mycotoxin producing fungi belong to
three genera: Aspergillus, Fusarium, and Penicillium. However,
not all species in these genera are toxicogenic
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II- Factors Affecting Mycotoxin Production
• Genetics and environmental and nutritional factors greatly affect the
formation of mycotoxins.
• Depending on the susceptibility of the crop, geographic and seasonal
factors, as well as cultivation, harvesting, storage, and transportation
practices, mycotoxins are found worldwide.
•
In the field, weather conditions, plant stress, invertebrate vectors,
species and spore load of infective fungi, variations within plant and
fungal species, and microbial competition all significantly affect
mycotoxin production.
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Continue Factors Affecting…….
• Physical factors such as time of exposure, temperature during
exposure, humidity, and extent of insect or other damage to the
commodity prior to exposure determine mycotoxin contamination
in the field or during storage.
• Chemical factors including the nutritional status of the crops or
chemicals (such as fungicides) used in crop management could
affect fungal populations, and consequently toxin production
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Continue Factors Affecting…….
• In general, mycotoxins are optimally produced at 24–28C, but some
toxins such as T-2 toxin is maximally produced at 15C.
• Contamination during crop storage may be affected by changes in
temperature and water activity, that allow ecological succession of
different fungi as water activity and temperature of stored grain
changes.
• During storage and transportation, water activity (aw), temperature,
crop damage, and a number of physical and chemical factors, such as
aeration (O2, CO2 levels), types of grains, pH, and presence or
absence of specific nutrients and inhibitors are important.
Water activity or aw was developed to account for the intensity with which water associates with various non-aqueous constituents and
solids. Simply stated, it is a measure of the energy status of the water in a system. It is defined as the vapor pressure of a liquid divided by
that of pure water at the same temperature; therefore, pure distilled water has a water activity of exactly one
III- The most important Mycotoxins
1) Aflatoxins
A
B
R3
R1
R1
R4
R2
C
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R1
D R1
Chemical Structure of Different Aflatoxins
Sources
Aspergillus flavus & A. paraciticus on Corn and peanuts
Factor favoring production of aflatoxins
a. Grain moisture
b. Tempreture
The optimal temperatures and water activity (aw) for the growth
of A. flavus and A. parasiticus are around 35–37C (range from 6–
54C) and 0.95 (range from 0.78–1.0), respectively; whereas for
aflatoxin production, they are 28–33C and 0.90–0.95 (range from
0.83 – 0.97), respectively.
Chemical characteristics
Exhibit intense blue or green fluorescence under UV.
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Toxicity
Mechanism of toxicological damage
hepatic steatosis Accumulation of
large vacuoles of triglyceride fat in
liver cells via the process of
steatosis
Pathogenesis Aflatoxicosis
Aflatoxin bind to guanine in deoxyribonucleic acid (DNA)
inhibiting the signal for the formation of massenger ribonucleic
acid (mRNA).
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Interruption of protein synthesis leads to deficiencies of structural
protein.
The long term effects of impaired protein synthesis include
hepatic steatosis and variety of metabolic and function
derangements like:
a. Loss of enzyme
b. Lack of formation of lipid acceptor protein in liver
c. Decreased cellulose digestion, volatile fatty acid
formation & proteolysis (breakdown of proteins )
d. Necrosis
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Young animals are more susceptible than adult and the
nutrition deficiency increase susceptibility
• Aflatoxins are mutagenic, teratogenic, and hepatocarcinogenic.
• Aflatoxin B1 is one of the most potent naturally occurring
carcinogen, extensive research was primarily done on this toxin.
The main target organ of AF is the liver.
• AFB1 also affects other organs and tissues including the lungs and
the entire respiratory system.
•
For the carcinogenic effects, rats, rainbow trout, monkeys, and
ducks are most susceptible and mice are relatively resistant.
• Consumption of AFB1-contaminated feed by dairy cows results in
the excretion of AFM1 in milk. AFM1, a hydroxylated metabolite
of AFB1, is about 10 times less toxic than AFB1; but its presence
in milk is of concern for human health.
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Impact on Human Health
• Whereas AFB1 has been found to be a potent carcinogen in
many animal species, the role of AF in carcinogenesis in
humans is complicated by hepatitis B virus (HBV) infections
in humans).
• Epidemiological studies have shown a strong positive
correlation between AF levels in the diet and primary
hepatocellular carcinoma.
•
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Since multiple factors are important in carcinogenesis and
environmental contaminants such as AFs and other
mycotoxins may, either in combination with HBV or
independently.
Diagnosis
• Clinical sign : decreased growth rate, reduced feed efficiency,,,
mild anemia, and increased susceptibility to infectious disease.
Treatment & Prevention
a. Detoxification : Hydrated sodium calcium aluminosilicate
(HSCAS) can absorb aflatoxins.
b. Supportive : Vitamin .E & selenium
c. Prevention
- Mold inhibitor
- Treatment of grain with anhydrous ammonia for 10-14 days.
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The Most Important Types of of Aflatoxins
At least 16 structurally related toxins in this group and the
most prominent of them are Aflatoxins B1, B2, G1, G2, M1and
M2.
They are produced by Asparagillus flavus and A.
parasiticus and infrequently A. pseudotamarii and A. nominus A.
ochraceoroseus has also been found to produce aflatoxins
Aflatoxin B1 is the most toxic in this group and is one of the
most potent naturally occurring carcinogens.
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Other significant members of the aflatoxin family, such as M1 and
M2, are metabolites of AFB1 and AFB2, respectively, and
originally isolated from animal urine, bovine milk or tissues.
Natural Occurrence
Aflatoxins have been found in corn, peanuts ّ‫ فول سوداني‬and peanut
products, cotton seeds, peppers, rice, pistachios, ‫ فستق‬tree nuts,
pumpkin ‫ قرع‬seeds, sunflower seeds and other oil seeds, copra,
‫ جوز هند‬spices, and dried fruits (figs, raisins).
Among these products, frequent contamination with high levels
of AF in peanuts, corn, and cottonseed, mostly due to infestation
with fungi in the field, are of most concern.
• Soybeans ‫الصويا‬, beans ‫الفاصولياء‬, pulses (Pea)‫البازالء‬, cassava ‫منيهوت‬,
sorghum ‫ الذرة‬, millet ‫الدخن‬, wheat ‫القمح‬, oats ‫القطن‬, barley ‫الشعير‬, and
rice‫ رز‬are resistant or only moderately susceptible to AF
contamination in the field.
•
It should be reiterated that resistance to AF contamination in the
field does not guarantee that the commodities are free of AF
contamination during storage. Inadequate storage conditions, such
as high moisture and warm temperatures (25–308C), can create
conditions favorable for the growth of fungus and production of AF.
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2) Ochratoxin & Citrinin
Sources :
Aspergillus orchraceus & Penicillium viridicatum
Mechanism of toxic
target the renal proximal tubule
- Disrupt protein synthesis
- Bind strongly to protein (albumin)
- Interfere with synthesis of tRNA & mRNA
- Disrupt carbohydrate metabolism
- Increase the generation of free radical
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Clinical sign
a. Acute : vomiting, diarrhea, dehydration & depression
b. Subacute to chronic : weight loss, feed efficiency, &
dehydration. Immunosupression, teratogenicity, carcinogenesis &
hemorrhage
‫تشوهات جنينية‬
The Most Important Types of Fungi
Ochratoxins, are produced by a number of fungi in the genera
Aspergillus and Penicillium. The largest amounts ochratoxins are
made by A. ochraceus and P. cyclopium.
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• Other fungi, such as Petromyces alliceus, Aspergillus ciricus, and
Aspergillus fonsecaeus (both in Aspergillus niger group), have also
been found to produce OA.
• Most of the OA producers are storage fungi and pre-harvest fungal
infection.
Factors affecting OA
• Although most OA producers can grow in a range from 37Cto 48C
and at aw as low as 0.78, optimal conditions for toxin production
are narrower with temperature at 24–25C and aw values .0.97.
Natural Occurrence
• Ochratoxins are produced primarily in cereal grains (barley, oats,
corn, wheat) and mixed feed during storage in temperate climatic
conditions, with levels higher than 1 ppm being reported.
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• OA has been found in other commodities, including beans, coffee,
nuts, olives, raisin, cheese, fish, pork, milk powder, fruit juices wine
beer, peppers.
• OA can be carried through the food chain because of the presence
of OA residues in animal products as result of its binding with
serum albumin.
• Natural occurrence of OA in kidneys, blood serum, blood sausage.
Structure of the ochratoxins.
• These metabolites form different classes depending on the
nature of the amide group, and the presence or absence of a
chlorine at R2 in the phenyl group.
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•
Ochratoxin A, the most toxic member of this group of
mycotoxins, has been found to causing kidney damage as well as
liver necrosis and enteritis (Small Intestine) in many animal
species.
•
The OA inhibits the activity of different enzymes like,
carboxypeptidase A, renal phosphoenolpyruvate carboxykinase,
phenylalaninetRNA synthetase, and phenylalanine hydroxylase.
•
Formation of free radicals has been considered as one of the
mechanisms for the carcinogenic/toxic effects of OA.
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3) Fumonisins
• Fumonisins (Fm) are a group of toxic metabolites produced
primarily by Fusarium verticillioides, F. proliferatum and other
related species readily colonize corn all over the world. Although F.
anthophilum, F. nupiforme, and F. nygamai are capable of producing
Fms.
• More than 11 structurally related Fms (B1, B2, B3, B4, C1, C4, A1,
A2, etc.), have been found since the discovery of FmB1.
• Fumonisins are most frequently found in corn, corn-based foods, and
other grains.
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• The level of contamination varies considerably with different
regions and year, ranging from negligible to more than 100
ppm; but is generally reported to be between 1 and 2 ppm.
•
FmB1 is the most common Fm in naturally contaminated
samples; FmB2 generally accounts for 1/3 or less of the total.
Although production of the toxin generally occurs in the field,
continued production of toxin during postharvest storage also
contributes to the overall levels.
Toxicological Effects
Fumonisin B1 is primarily a hepatotoxin and carcinogen in rats.
Feeding culture material from F. verticillioides or pure FmB1 to rats
resulted in cirrhosis and hepatic nodules, carcinoma.
‫ي‬
ّ ‫تليّف كبد‬
Kidney is also a target organ.
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Mechanistically, Fms are inhibitors of ceramide synthase
(sphinganine/sphingosine N-acyltransferase), a key enzyme
involved in the biosynthesis of sphingolipids, which are heavily
involved in cellular regulation, including cell differentiation,
mitogenesis and apoptosis
The ability of FmB1 to alter gene expression and signal
transduction pathways are considered necessary for its
carcinogenic and toxic effects.
4) Trichothecenes (TCTCs)
a) T-2 toxin,
b) Deoxynivalenol (DON)
Several species of Fusaria infect corn, wheat, barley, and rice.
Under favorable conditions, they elaborate a number of different
types of mycotoxins, more than 100 TCTCs have been identified.
Only a few frequently found in foods and feeds are potentially
hazardous to human and animal health.
Trichothecenes
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chemical structure of the side chain.
Other fungal genera elaborate TCTCs are: Myrothecium,
Trichoderma, Trichothecium, Cephalosporium, Verticimonosporium,
and Stachybotrys.
The TCTC mycotoxicoses affect many organs, including the
gastrointestinal tract, nervous, immune, hepatobiliary, and
cardiovascular systems.
Mechanistically, inhibition of protein synthesis is one of the earlier
events in manifestation of TCTC toxic effects and they act at
different steps in the translation process.
Inhibitory effects of these mycotoxins vary considerably with the
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4-a) T-2 toxin
T-2 toxin, a highly toxic type of A TCTC. It is produced by F.
tricinctum, F. sporotrichioides (major), F. poae, F. sulphureum, F.
acuminatum, and F. sambucinum.
Unlike most mycotoxins, which are usually synthesized near 25C,
the optimal temperature for T-2 toxin production is around 15C.
Almost all the major TCTCs, including T-2 toxin, are cytotoxic and
cause hemorrhage, edema, and necrosis of skin tissues.
4-b) Deoxynivalenol (DON)
The DON is a major type B TCTC mycotoxin produced by:
F. graminearum (major) and other related fungi such as F.
culmorum and F. crookwellense.
Because DON causes feed refusal and emesis in swine, the name
“vomitoxin” is also used for this mycotoxin.
Worldwide frequent natural occurrence of DON in cereal grains
has been reported.
Contamination of this toxin in corn and wheat is generally high.
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• Although inadequate storage may lead to the production of
some TCTC mycotoxins, infestation of Fusaria in wheat and
corn in the field is of most concern for the DON problem
• With wet and cold weather during maturation, grains are
especially susceptible to F. graminearum infection.
•
The optimal temperature for DON production is about 24C.
• Toxicologically, DON induces anorexia and emesis both in
humans and animals.
• Swine are most sensitive to feed contaminated with DON.
Whereas most TCTCs are immunosuppressors.
• DON is a hyperinducer of cytokines.
Edema is an abnormal accumulation of fluid beneath the skin
Anorexia is the symptom of poor appetite
Cytokines are small cell-signaling protein molecules that are secreted by cells of the nervous system
5) Zearalenone
Sources:
Fusarium roseum and F. graminearum on corn, wheat, barley &
oats
Factor favoring production
a. High moisture 22% - 25%
b. Alternating high and low temp. (7-21 ๐c)
Mechanism of toxicological damage
a. initiating specific RNA synthesis
b. Function as a weak estrogen.
Toxicity
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a. Swine are most susceptible
b. low for all effects except reproductive function.
6) Ergot
Source : Claviceps purpurea on barley, wheat & oats
Factor favoring : Warm & humid
Clinical sign
a. necrosis of the feet, ears and tail
b. increased temperature., pulse & respiration rate
c. lactation does not occur
d. hyper-excitability & tremors
e. heat intolerance in cattle
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Dopamine a simple organic chemical
Dopamine plays a major role in the brain system that is responsible for rewarddriven learning
Several important diseases of the nervous system are associated with
dysfunctions of the dopamine system
Parkinson's disease
Mechanism of toxic
a. potent initiators of contraction in smooth muscle
b. mimic the action of dopamine.
Treatment
a. animals should be provided with a warm, clean, stress-free
environment
b. control secondary bacterial infection
c. milk supplement
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Mycotoxins and food chain
Fungal contamination
Vegetables
Many accidents
Animal
Production
Elimination
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rare accidents (cancer)
Man
Products
(Animal origin)
I- Preventive Measures
Management of Mycotoxin Contamination
• The economic implications of the mycotoxin problem and its
potential health threat to humans have clearly created a need to
eliminate or at least minimize mycotoxin contamination of food
and feed.
• While an association between mycotoxin contamination and
inadequate storage conditions has long been recognized, studies
have revealed that seeds are contaminated with mycotoxins prior to
harvest. Therefore, management of mycotoxin contamination in
commodities must include both pre- and post- harvest control
measures
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I-A- Pre-harvest Control
• Mycotoxin contamination can be reduced somewhat by using of
resistant varieties (most effective, but not all are successful) and
earlier harvest varieties:
– crop rotation,
– adequate irrigation,
– control of insect pests.
•
Significant control of toxin contamination is expected to be
dependent on a detailed understanding of the:
– physiological and environmental factors that affect the biosynthesis
of the toxin,
– the biology and ecology of the fungus,
– the parameters of the host plant–fungal interactions.
Efforts are underway to study these parameters primarily for the
most agriculturally significant toxins, namely AFs, Fms, and TCTCs
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• Use of atoxigenic biocompetitive, native A. flavus strains to outcompete the toxigenic isolates has been effective in significantly
reducing preharvest contamination with aflatoxin in cotton and
peanuts.
• However, the aflatoxin contamination process is so complex that a
combination of approaches will be required to eliminate or even
control the preharvest toxin contamination problem.
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I-B- Post-harvest Control
•
After harvest, crop should not be allowed to over-winter in the
field as well as subjected to birds and insects damage or
mechanical damage.
•
Grains should be cleaned and dried quickly to less than 10–
13% moisture and stored in a clean area to avoid insect and
rodent infestation.
•
Postharvest mycotoxin contamination is prevalent in most
tropical countries due to:
•
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subadequate methods of harvesting,
a hot, wet climate coupled with handling, and storage
practices which often lead to severe fungal growth and
mycotoxin contamination of food and feed.
• Sometimes contaminated food has been diverted to animal feed to
prevent economic losses and health concerns. However, this is
not a solution to the contamination problem.
• Irradiation has been suggested as a possible means of controlling
insect and microbial populations in stored food, and
consequently, reducing the hazard of mycotoxin production under
these conditions .
• Significant emphasis has been placed on detoxification methods
to eliminate the toxins from the contaminated lots or at least
reduce the toxin hazards by bringing down the mycotoxin levels
under the acceptable limits.
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II- Removal or Elimination of Mycotoxins.
• Since most of the mycotoxin burden in contaminated commodities
is localized to a relatively small number or seeds or kernels,
removal of these contaminated seeds/kernels is effective in
detoxifying the commodity.
• Methods currently used include removal by :
(a) filtration and adsorption onto filter pads, clays,
activated charcoal, etc.,
(b) solvent extraction removal of the mycotoxin by some
specific solvent
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(c) physical separation by:
-identification and removal of damaged seed;
-mechanical or electronic sorting;
-flotation and density separation of damaged or
contaminated seed;
-physical screening and subsequent removal of damaged
kernels by air blowing;
-washing with water
- use of specific gravity methods
All these methods have shown some effect for some
mycotoxins, including DON, FmB, AFB1
III- Inactivation of Mycotoxins.
When removal or elimination of mycotoxins is not possible,
mycotoxins can be inactivated by:
(a) physical methods such as thermal inactivation, photochemical
or gamma irradiation,
(b) chemical methods such a treatment of commodities with acids,
alkalies, aldehydes, oxidizing agents, and gases like chlorine,
sulfur dioxide, NaNO2, ozone and ammonia,
(c) biological methods such as fermentations and enzymatic
digestion that cause the breakdown of mycotoxins.
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• The commercial application of some of these detoxifying
mechanisms is not feasible because, in a number of cases, the
methods will be limited by factors such as:
• the toxicity of the detoxifying agent, nutritional or aesthetic
losses of commodities during treatment, and the cost of the
sophisticated treatment
• Although several detoxification methods have been established for
aflatoxins, only the ammoniation process is an effective and
practical method.
• Other chemicals such as ozone, chlorine, and bisulfite have been
tested and some effect for some mycotoxins was shown in it.
• Solvent extractions have been shown to be effective but are not
economically feasible.
IV- Avoiding Human Exposure
Role of Rigorous Monitoring Programs
A tolerance level of 1 ppm for DON in grains for human
consumption has been set by a number of countries, including the
United States. The FmB1 levels established by FDA in 2000 are
limited to 5, 20, 60 100, 30, and 10 ppm, in corn and corn byproducts to be used for horse and rabbit, catfish and swine, and
mink, poultry, respectively.
Among 77 countries which have regulations for different
mycotoxins, eight have specific regulations for OA, with limits
ranging from 1 to 20 mg/kg in different foods.
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CONCLUSIONS
• Mycotoxins are low molecular weight secondary metabolites
of fungi that are contaminants of agricultural commodities,
foods, and feeds.
• Fungi that produce these toxins do so both prior to harvest and
during storage. Although contamination of commodities by
toxigenic fungi occurs frequently in areas with a hot and
humid climate, they can also be found in temperate conditions.
• Production of mycotoxins is dependent upon the type of
producing fungus and environmental conditions such as the
substrate, water activity (moisture and relative humidity),
duration of exposure to stress conditions, and microbial,
insect, or other animal interactions.
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• Although occurrences of mycotoxicoses in humans have been
documented, several of these have not been well characterized,
neither has a direct correlation between the mycotoxin and
resulting toxic effect been well established in vivo.
• Even though the specific modes of action of most of the toxins are
not well established, acute and chronic effects in prokaryotic and
eukaryotic systems, including humans have been reported.
• The toxicity of the mycotoxins varies considerably with the toxin,
the animal species exposed to it, and the extent of exposure, age,
and nutritional status.
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• Most of the toxic effects of mycotoxins are limited to specific
organs, but several mycotoxins affect many organs. Induction of
cancer by some mycotoxins is a major concern as a chronic effect
of these toxins.
• It is nearly impossible to eliminate mycotoxins from food and feed
in spite of the regulatory efforts at the national and international
levels to remove the contaminated commodities.
This is because mycotoxins are highly stable compounds, the
producing fungi are ubiquitous, and food contamination can occur
both before and after harvest. Nevertheless, good farm
management practices and adequate storage facilities minimize the
toxin contamination problems.
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• A combination of natural biocontrol competition fungi and
enhancement of host-resistance against fungal growth or toxin
production could prevent toxin formation to a very significant extent.
• Rigorous programs for reducing the risk of human and animal
exposure to contaminated food and feed also include:
• economically feasible
• safe detoxification processes
• dietary modifications.
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• Additional, systematic epidemiological data for human exposure
is needed for establishing toxicological parameters for
mycotoxins and the safe dose for humans.
• It is unreasonable to expect complete elimination of the
mycotoxin problem, but multiple approaches will be needed to
minimize the negative economic impact of the toxins on the entire
agriculture industry as well as their harmful effects on human and
animal health.
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