Natural toxins

Natural toxins are chemicals with potentially toxic effects on human beings because
of their natural occurrence in food.
Usually, natural toxins are not acutely toxic, except in a few cases in animals. An
example is tetrodotoxin , a neurotoxin first identified in puffer fish. Expert cleaning
of the fish prevents transmission of the toxin to the edible parts of the fish. Yet,
accidents happen each year.
Most of the natural toxins, particularly those occurring in plant-derived foods,
induce adverse effects only after chronic ingestion or by allergic reactions.
Natural toxins include:-

1) Endogenous toxins of plant origin.

2) contaminants of natural origin.

3) toxins of microbial origin.

1) Endogenous toxins of plant origin

There is no simple way of classifying toxic food components of plant origin since this
category comprises many different types of substances. These are classified based on
common functional groups (toxic phenolic substances, cyanogenic glycosides, and
glucosinolates), physiological action (acetylcholinesterase inhibitors) and type of effect
(biogenic amines and central stimulants). Several important examples of the various types
will be highlighted in this lecture.
1. Toxic phenolic substances:-
- More than 800 phenolic substances have been detected in plants. Many of them
contribute to the (bitter) taste and flavor of foods, and some also contribute to color.
- These substances can be divided into two major groups based on frequency of
occurrence, structural relationship, and relative toxicity:
a- Widespread phenolic plant substances, often used in the production of foods and
beverages. About 25 have been identified and only a few are present in relatively high
concentrations in certain plant foodstuffs; the majority are only present in trace amounts.
 This group includes phenolic acids such as caffeic acid, ferulic acid, gallic acid,
flavonoids, lignin, hydrolysable, condensed tannins, and derivatives. At the levels
present in food, these substances are devoid of acute toxicity.
b- More heterogeneous group of highly toxic phenolic substances. Examples are coumarin,
safrole, myristicin, and phenolic amines also known as catecholamines and gossypol.
- A number of phenolic substances will be discussed in more detail in the following :
a) Flavonoids:-
- A class of plant pigments that are widely present in human food, are the flavonoids.
These pigments are polyhydroxy-2-phenylbenzo-γ-pyrone derivatives, occurring as
aglycones, glycosides and methyl ethers. They are divided into six main subgroups
(Fig. 1)

Fig. 1. The structure of the flavonoids.

- Most flavonoids are present as β-glucosides.

- Because of their wide distribution, the effects of the flavonoids on human well-being
are of considerable interest. More than 1 g of various flavonoids are ingested daily in
the diet of the Western world.
- The flavones are group of yellow pigments that occur abundantly. Examples are
nobiletin, tangeretin (which are found in citrus fruits) and heptamethoxyflavone.
- The flavones group has been extensively investigated for mutagenicity. Quercetin is
the only flavonoid shown to be carcinogenic in mammals after oral administration.
b) Tannins:-
- Tannins are a heterogeneous group of broadly distributed substances of plant origin.
They are considered to include all polyhydric phenols of plant origin with a molecular
weight higher than 500.
- Two types of tannins can be distinguished based on degradation behavior and botanical
distribution, namely hydrolyzable tannins and condensed tannins.
- The hydrolyzable tannins are gallic, digallic, and ellagic acid esters of glucose. An
example of this group is tannic acid, also known as gallotannic acid or gallotannin.
Tannic acid has been reported to cause acute liver injury, i.e., liver necrosis and fatty
liver.

- The condensed tannins are flavonoids. They are polymers of leukoanthocyanidins.

- Tannins occur in many tropical fruits, tea, coffee, and cocoa. Tea has the highest tannin
content. It has been shown that on maximum extraction, black tea leads to 431 to 450
mg tannin / cup. It can be estimated that a person may ingest 1 g or more tannins / day.
c) Coumarin, safrole and myristicin:-
- Natural toxins can also be found among the flavorings such as coumarin, a chroman
derivative, safrole and myristicin, both methylenedioxyphenyl substances.
- Coumarin widely occurs in a number of natural flavorings, including cassis, lavender,
and lovage. These flavorings are extensively used in sweets and liquors. Traces of
coumarin occur in citrus oils and some edible fruits.
- Safrole has been shown to cause liver tumors in rats. It is found in black peppers.
Safrole is still allowed for food use in the European Community, while it is prohibited
in the US though, as they have been found to cause liver damage in rats.
- Myristicin is found in spices and herbs such as nutmeg, black pepper, carrot, parsley,
celery, and dill. It has been suggested that myristicin contributes to the toxicity of
nutmeg. After nutmeg abuse, tachycardia, failing salivation, and excitation of the
central nervous system have been reported.
2. Cyanogenic glycosides:-
- Cyanogenic glycosides are glycosides from which cyanide is formed by the activity of
hydrolytic enzymes. They are widely spread in higher plants such as lima beans and
cassava.
- Cyanide doses that are lethal to humans can easily be reached or even exceeded after
the intake of a variety of cyanogenic foodstuffs. Lethal doses by humans range from
0.5 to 3.5 mg / kg body weight. The quantities of cyanide produced by Asiatic varieties
of lima beans range from 200 to 300 mg / 100 g . American varieties of lima beans
produce less than 20 mg HCN / 100 g. Selected breeding of low-cyanide varieties has
been started.
- Cyanogenic glycosides consist of a saccharide moiety and an aglycone, a β-
hydroxynitrile. The saccharide group can be a monosaccharide or a disaccharide.
Glycoside linkages can be hydrolyzed by glycosidases. The nitrile can undergo further
degradation by a lyase to hydrogen cyanide and an aldehyde, a ketone or in some cases
an acid.
- An example of cyanogenic glycosides is linamarin which found in lima beans and
cassava and consists of α-hydroxyisobutyronitrile and D-glucose. Fig. 2 shows
equations for cyanogenic glucoside linamarin degradation.

Fig. 2. Degradation of the cyanogenic glucoside linamarin.

- Glycosidases and hydroxynitrile lyase are present in plant cells. They become available
when plant tissue is damaged. This inevitably occurs when food is prepared for
consumption.
- Cassava is rich in starch and an important food source in Africa, parts of Asia and Latin
America, so preparation methods have been developed by which the cyanogenic
glycosides are removed or hydrolyzed, and β-glucosidase is destroyed. The cassava is
grated, soaked in water, and fermented for several days. The soaked plant tissue is then
 dried and pounded to flour. Such processes greatly reduce the cyanogen content of food
to safe levels. For example, “gari,” a fermented cassava preparation, contains an
average of 1.0 mg HCN / 100 g. High consumption of dry, unfermented cassava,
containing high levels of cyanogen, accounts for the widespread incidence of goiter in
parts of Africa as the cyanide formed can be metabolized to thiocyanate by the enzyme
rhodanase.

3. Glucosinolates:-
- Glucosinolates are group of substances occurring in cruciferous plants, such as cabbage
and turnips. They can be considered as natural toxins, but also as antinutritives.
- Concerning toxicity and antinutritive activity, the hydrolysis products are the active
agents, not the glucosinolates themselves. Hydrolysis of glucosinolates results in the
formation of isothiocyanates , thiocyanate and nitriles. The enzyme becomes available
for catalysis when cells are damaged on cutting or chewing. Fig. 3 shows general
structures of glucosinolates and its hydrolysis products.

Fig. 3.General structure of glucosinolates and its hydrolysis products.

- Several isothiocyanates have been shown to be embryotoxic in rats. Further, several

nitriles have been identified as precursors of N-nitroso compounds.
- Generally , glucosinolates will be explained in detail in the antinutritives lecture.

4. Acetylcholinesterase inhibitors:-
- These active components are alkaloids.
- Acetylcholinesterase inhibitors have been detected in several edible fruits and vegetables.
- These include broccoli, Valencia oranges, sugar beet, cabbage, pepper, carrot, strawberry,
apple, lima bean, and radish. In potato, eggplant, and tomato — members of the
Solanaceae family.
a) Solanine:-
- The most potent inhibitors are found in potatoes, and of these the most active component
is the glycoalkaloid solanine.
• The toxicity of solanine has been the subject of extensive study. Oral administration
results primarily in gastrointestinal and neurological symptoms.
• Commercial potatoes contain 2 to 15 mg of solanine /100 g fresh weight. Greening of
potatoes may increase the solanine content to 80 to 100 mg /100 g. Most of the alkaloid
is concentrated in the skin. Sprouts may contain lethal amounts of solanine.
• Solanine is heat stable and insoluble in water. Hence, toxic potatoes cannot be rendered
harmless by cooking.
• It is accepted that 20 mg solanine /100 g fresh weight is the upper safety limit.
b) Chaconine and tomatine:
Since potatoes also contain other glycoalkaloids, namely chaconine and tomatine, with
biological properties like solanine, the symptoms seen in potato poisoning may be due to
combined actions of the alkaloids. All existing and newly developed varieties of potatoes
are now monitored for alkaloid content. Solanine is heat stable and insoluble in water.
Hence, toxic potatoes cannot be rendered harmless by cooking. It is generally accepted that
20 mg solanine per 100 g fresh weight is the upper safety limit.

5. Biogenic amines:-
Natural toxins also include certain amines which can be of plant as well as of microbial
origin. The most important biogenic amines found in plants are Dopamine, Epinephrine,
Norepinephrine, Serotonin, and Tyramine.
The dietary intake of biogenic amines may pose risks. A well-known harmful effect of all
three of the phenethylamines, dopamine, norepinephrine, and tyramine is hypertension.
The risk is greater when combinations of biogenic amines and monoamine oxidase (MAO)
inhibitors are ingested. Monoamine oxidases mediate the oxidative deamination of the
three phenethylamines. Monoamine oxidase inhibitors are a heterogeneous group of drugs.
Clinically used MAO inhibitors include hydrazine derivatives such as the antidepressent
iproniazid. Several phenalkylamines are found in citrus fruits.
Amines may be formed by the metabolic transformation of precursors endogenously
present in food of plant origin. Fava beans (Vicia faba) contain dihydroxyphenylalanine
(DOPA), which may be decarboxylated to dopamine.
6. Central stimulants:-
- For most people the everyday diet contains a considerable amount of stimulants. These
substances increase the state of activity of the nervous system. A particular class of
stimulants is the methylxanthines. They include caffeine, theophylline, and
theobromine.
- Caffeine is found in coffee beans, tea leaves, cocoa beans, and cola nuts. In our diet the
primary source of caffeine is coffee: one cup of coffee is estimated to contain 100 to
150 mg of caffeine. Theophylline is present in small amounts in tea. Theobromine is
the principal alkaloid of the cocoa bean. It is also found in tea leaves and cola nuts.
- In general, methylxanthines cause effects on the peripheral nervous system, but they
also induce significant stimulation of the central nervous system. Caffeine is a little
more potent than theophylline, and theobromine is relatively inactive. Further, caffeine
has been reported to cause premature aging, a lower growth rate and a lower body
weight in experimental animals.
2) Natural contaminants:-
- There are three important sources:-
1. Contamination resulting from mixing of edible plants toxic nonnutritive plant.
2. Contamination resulting from intake of toxic substances by animals.
3. Microbial toxins.
1. Contamination resulting from mixing of edible plants toxic nonnutritive plant:-
- Several intoxications have been reported following the consumption of contaminated
cereals. The causative agents are pyrrolizidine alkaloids, produced by the genera
Senecio, Crotalaria and Heliotropium.
- Pyrrolizidine alkaloids can be the cause of acute liver damage and vein lesions. These
substances may also contribute to the liver cancer incidence in humans.
- Epidemics of pyrrolizidine intoxication have been reported in India and Afghanistan
in 1973 and 1976.
- In India, millet, the principal cereal in the diet, appeared to be heavily contaminated
with Crotalaria seeds. In Afghanistan, the consumption of wheat bread heavily
contaminated with Heliotropium seeds was found to be the cause of the intoxication.
2. Contamination resulting from the intake of toxic substances by animals:-
- Contamination of meat with toxic substances of plant origin rarely occurs. Only
in a few cases the intoxication appeared to be related to the consumption of
wild animals which had ingested highly toxic plant material shortly before
they were consumed. Toxic contaminants in milk and aquatic organisms can
originate from feed.
a) Contamination of milk with plant toxins:-
- Milk is readily contaminated when lactating animals ingest toxins. Especially
during periods of drought, when feed plants are scarce and the weeds are in
flower, the milk may contain sufficient toxin to give rise to outbreaks of “milk
sickness.” In this case, the major toxic component appeared to be tremetone.
- The symptoms were weakness, followed by anorexia, abdominal pain,
vomiting, muscle tremor, delirium, coma, and eventually death. The mortality
rate was between 10 and 25%.

b) Natural toxins in aquatic organisms:-

- Contamination of seafood with phycotoxins and the resultant effect on human
health is a world- wide problem.
- Seafood poisoning is often associated with the occurrence of algal "
blooms" where the microscopic algae may reach sufficient density to produce
a visible discoloration
- From the resulting types of poisoning:-

1) Paralytic shellfish poisoning(PSP):-

• Paralytic shellfish poisoning (PSP) is attributed to the consumption of
shellfish such as mussels that have become contaminated with a toxin or
 group of toxins such as saxitoxin from the ingestion of toxic plankton, in
particular toxic dinoflagellates belonging to the genera such as Alexandrium
and Gymnodinium.
• PSP symptoms include tingling and burning in face, lips, tongue, and
ultimately the whole body, and numbness, general motor incoordination,
confusion, and headache. These symptoms develop within 30 min. after
ingestion. Death, preceded by respiratory paralysis, occurs within 12 hrs.
2) Diarrhetic shellfish poisoning (DSP):-
• Diarrhetic shellfish poisoning (DSP) is caused primarily by eating shellfish,
such as mussels contamintated with okadiac acid and / or dinophysistoxins
which orginate mainly from certain Dinophysis species.
• DSP symptoms include gasaterointestinal disturbance ( include diarrhea,
nausea, vomting and abdominal pain). These symptoms develop within 30
min. to a few hours after ingestion.
- Red tide:-
• In many parts of the world, the sea sometimes suddenly becomes colored, as
a result of dinoflagellate bloom. The phenomenon is referred to as red tide,
although the bloom may be reddish, yellowish, brownish, greenish or bluish
in color. The red color is probably due to the xanthophyll peridinin. The
chance of contamination and poisoning is highest during a red tide.
• In spite of the frequent occurrence of red tide and the high toxicity of the
paralytic shellfish poisons, intoxication rarely occurs. This is largely due to
strict regulations set by many countries and the awareness in coastal areas of
the risks associated with eating shellfish during red tides.
- Effect of thermal processing on phycotoxins :-
Although ordinary cooking destroys up to 70% of the toxin(s) and pan-frying
destroys even more, there may be sufficient toxin left in the mollusks to cause
serious poisoning.
 3) toxins of microbial origin

- Microorganisms are ubiquitous. Absence of microorganisms in an environment

indicates that special or unusual conditions have occurred, such as heating and
filtration for sterilization or preservation.
- Food-borne diseases can be either food-borne infections or food-borne
intoxications, depending on whether the pathogen itself or its toxic product (a
microbial toxin or toxic metabolite, produced in the food) is the causal agent.
- Microbial agents causing food-borne intoxications include toxins produced by
bacteria, fungi (mycotoxins) and algae and toxic metabolites such as biogenic
amines and ethyl carbamate produced by bacteria and yeasts.

Fig. 4 : Classification of food-borne diseases.

 1) Bacterial toxins:-
According to the mechanisms underlying the effects of bacterial toxins, they can be classified as
follows:
a) Sub-unit toxins (e.g., Clostridium botulinum toxins).
b) Membrane-affecting toxins (e.g., Staphylococcus aureus toxins).
c) Lesion-causing toxins (e.g., Clostridium perfringens and Bacillus cereus toxins).
d) Immuno-active endotoxins (e.g., Gram-negative bacteria toxins).

2) Mycotoxins:-
− Mycotoxins are secondary metabolites of fungi which can induce acute as well as chronic toxic
effects in animals and man. Currently, a few hundred mycotoxins are known, often produced by the
genera Aspergillus, Penicillium and Fusarium.
− Mycotoxin contamination of food and feed highly depends on the environmental conditions that
lead to mold growth and toxin production.
The mycotoxins are aflatoxins, deoxynivalenol , ergot alkaloids, patulin, sterigmatocystin, zearalenone and
ochratoxin A.

3) Toxic microbial metabolites:-

a) Biogenic amines:
- The main producers of biogenic amines in foods are Enterobacteriaceae and Enterococci.

b) Ethyl carbamate:
- Ethyl carbamate (urethane) is associated with yeast fermented foods and beverages.
Toxicity:
- Ethyl carbamate is a mutagen as well as a carcinogen.