Mycotoxins and human health risks an overview

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Subhkij Angsubhakorn



This is a review and brief historical report of mycotoxins as risks to human health. Mycotoxins are recorded in history as far back as 5,000 years ago in China. Besides ergot and mushroom poisonings, reports as early 1861, indicate that a suspected mycotoxin affecting humans was reported in Russia, and 1891, there was a report of mouldy rice in Japan to be toxic to man. This review reports on the early literature on mycotoxins affecting human up to 1960, which is the time of the discovery of aflatoxin, and to our present knowledge where this problem still persists.



All reviews described here deal with fungi that are toxic in one way or another, either the fungi are themselves toxic when consumed, as either poisonous mushrooms or ergot, or the fungi, as they grow, secrete toxic compounds that diffuse into the substrate on which they are growing and so make it toxic when eaten. Antibiotics which are produced by fungi are mycotoxin too, but in general usage, this term is applied to compounds that are toxic to microbes.




Poisonous mushrooms (toadstool), which are called mycetismus, have been known, written and talked about for well over two thousand years. The Amanita phalloides group is estimated to be responsible for 95 percent of the fatal cases of mushroom poisoning throughout the world. An outbreak of mass poisoning occurred near Poznan, Poland, in 1918, in which 31 school children died from eating a dish of mushrooms containing this fungus-presumably in their school lunch (Simons, 1971). A. phalloides evidently is more common in Europe, and A. Verna and its varieties are more common in the United States.


Higher fungi such as the Amanita phalloides group is estimated to be responsible for 95 percent of fatal cases of mushroom poisoning throughout the world.

Higher fungi such as Amanita phalloides group is estimated to be responsible for 95 percent of fatal case of mushroom poisoning through-trout the world.


All the substances are cyclic polypeptides with molecular weights varying from about 800 to 1100.

The lethal dose of amanithins is about 0.1 g/kg body weight and 1-2 mg/kg body weight for phalloidin. A. phalloides Captophores contain around 10, 8, 7 and 1.5 mg of phallodin, alpha-amanitin, beta-amanitin and gamma-amanitin, respectively per 100 9 of fresh tissue.

Clinical Symptoms

There are two groups of toxins that are present in these muhrooms—the phallotoxins, composed of phallin and phalloidin, and the amanitins, made up of alpha amanitin and beta amanitin.

The gastro-intestinal symptoms, which appear first and some hours after the mushrooms are consumed, are produced by the phallotoxins. The amanitins are 10 to 20 times as toxic as the phallotoxins, and cause the hepatorenal damage that results in the symptoms appearing later and that in many cases ends in death.

There is a characteristic latency of 6 to 15 or even 20 hours. The illness begins as a severe gastroenteritis, sometimes with associated cardiovascular collapse, prostration, delirium and coma, but after a day or two the patient often seems to improve. The most characteristic manifestations do not occur until the third or fourth day after the ingestion, when jaundice and other signs of hepatic cell necrosis appear. Severe damage may also arise in the renal tubular epithelium, myocardium and brain. Death may occur with 5 to 10 days; it is due to liver and renal failure, cerebral damage or with attending coma or cardiac arrest.




Infection of grasses and cereals with fungal species of genus Claviceps produces sclerotia (compact hyphal structure). The pharmacological properties of ergot were recognized in the latter part of the 16th century, and about 100 years later, cereal grains containing ergot were shown to be the cause of these epidemics in Europe.

In 1951 there was an outbreak of "bread poisoning" in a small town in France. Apparently moldy rye was sold illegally (to avoid a grain tax) in central France to a miller, who ground the rye and mixed it with flour which he then sold to a baker.

On August 15, 1951, many people ate small amounts of bread which may have been made from this contaminated flour. About 200 people became ill, as did many domestic animals. dogs, cats, poultry, fish, fed the same bread. A total of 25 people suffered severe delirium, and four people, one previously healthy young man and three old people suffered severe delirium. A recent outbreak occurred in Ethiopia, 97 of 42,000 people developed gangrenous ergotism. (King, 1979).


Claviceps purpura is the common ergot on rye and wheat. The fungus lives over winter in the form of sclerotium, a dense mass of fungus cells. Usually the sclerotia are somewhat larger and also less dense than the seeds of the host plant on which they are borne.


The ergot alkaloids are derivatives of Iysergic acid (ergotamine), isolysergic acid (ergocristine) or dimethyl ergoline (agoclacine). Pharmacologically, these compounds are rapid acting, powerful oxytoxics, i.e., they stimulate the smooth muscle of the uterus. They are also weak vaso-constrictors.

Clinical Symptoms

Descriptions of ergot poisoning written in the Middle Ages were quite vivid. There were severe internal feeling of heat and intense thirst, multiple ulcerations of skin, a burning sensation of the limbs, the feeling of ants and mice crawling underneath the skin, the drying and turning black of hands, arms, feet and legs, blindness, dementia and mental degeneration.

Acute ergot poisoning today is essentially a problem only in chemotherapy and rarely has it occurred recently as a result of eating. The symptoms include vomiting, diarrhea, intense thirst, a tingling, itchy and cold skin, a rapid, weak pulse, confusion, and unconciousness.

Chronic ergot poisoning today seems limited to accidents in treating patients for migraine headaches. The extremities, especially the feet and legs, become cold, pale, and numb because of the constriction of the local blood vessels and result in diminished blood flow. Walking becomes painful and eventually gangrene develops.




In 1961, Birmingham et a/ reported a phototoxic dermatitis which had been shown to be endemic among white harvesters of celery. It was believed that exposure to celery oil and sunlight was reponsible for the dermatitis. Also, it was noted that the dermatitis was more severe when rotted celery was handled. Experimentally, only extracts of rotted celery produced the characteristic blistering lesions of celery dermatitis.


Celery rot ("pink rot") is a fungus disease produced by Sclerotinia sclerotiorum.


Two psoralens were isolated and identified from "pink rot" celery which were not delectable in healthy extracts. The psoralens and a group of linear furocoumarins containing a furan ring fuse at the 2, 3 position to the c-6 and c-7 of the coumarin structure.

Clinical Symptoms

The affected areas were the hands and forearms, but the lower legs, chest, abdomen, and back also affected if the worker wore shorts and no shirt. The lesions healed, with depigmentation and lasting many months. The incidence was said to be greater after a rain and before the use of fungicides to control fungal growth on the celery.

Psoralens, especially 8 - methoxypsoralen and trimethypsoralen have been used successfully to treat vitiligo, which is a progressive, localized achromania of the skin resulting from a functional abnormality of the melanocytes, apparently due to the loss of function of the tyrosinase system.

In apparent careless use of psoralens as suntanning agents to augment the tanning capabilities of the skin, excessive amounts of the agents were used, and after exposure to the sun, a severe dermatitis developed.

Nausea, vomiting, vertigo, and mental excitation resulted from ingestion of 20 mg or more of 8methoxypsoralen; whether liver damage resulted is still an unsolved question (Becker, 1960).




The bulk of the literature on blood-forming disease is written in Russian, for it is in the Soviet Union that the disease has been a problem. Perhaps as early as 1913, a food - borne disease, possibly from eating fusarium - contaminated bread, occurred in Siberia. During the war years of 1941-1945 larger outbreaks occurred more frequently than in the 1930, is involving several districts in Western Siberia and European Soviet Russia.

Soon the toxicity of rye was related to the growth of toxigenic strains of Fusarium on the cereal seed which absorbed much moisture and provided a suitable medium for the growth of cryophilic fungi.

It has been suggested that the epoxytrichothecenes, T-2 toxin, played a role in Russian alimentary toxic aleukia (Bamburg, et al. 1969). It is shown that T-2 poisoning in chickens resembles the mycotoxin poisoning associated with Russian overwintered grain.


The trichothecenes are produced by various species of Fusarium especially Fusarium graminearum (F. roseum), F. moniliforme, etc.


The trichothecenes are a complex group of sesquiterpenoids containing the trichothecane nucleus, characterized by an olefinic bond at the 9, 10 position and an epoxy group at the 12, 13 position.

Clinical Symptoms

The Russian descriptions of the disease, dividing the clinical feature into four stages, indicate that the disease seems to result from toxic injury to the hematopoletic, autonomic nervous, and endocrine systems.

First Stage

This Is a rapid onset of irritation to the upper gastrointertinal tract, begining a few hours after ingestion of the toxic cereal product, often bread. The contaminated food would have a peppery taste and produce a burning sensation from the mouth to the stomach. Within a few days, the patient develops acute gastro-enteritis, with nausea, vomiting and diarrhea, This local effect persists for 3 to 9 days and then spontaneously ends, even when the victim continues to eat the poisoned grain.

Second Stage

A slow degeneration of the bone marrow occurs within 9 weeks. Visible skin hemorrhage appears and hematologic examination reveals a marked decrease in the total number of leukocytes. Before hemorrhages appear, some patients display nervous system problems: irritation, weakness, fatique, vertigo, headache, palpitation and slight asthma.

Third Stage

The most serious stage comes about suddenly and has four essential features:

  1. Hemorrhagic syndromes begin with petechial hemorrhage on the skin, axilliary and inguinal areas, arms, thighs, face and head.
  2. Necrosis begins in the throat and spreads throughout the mouth and into the larynx, vocal cords, lungs stomach and bowels.
  3. Impaired hematopoletic and reticuloendothelial systems permit widespread bacterial infection in the necrotic areas. Lympnhodes become enlarged.
  4. Laryngeal edema and stenosis of the glottis cause by esophageal lesion, resulting in death because of asphyxiation.

Fourth Stage

Recovery period if clinical help is provided in time.




Epidemics of an acute heart disease broke out in rural Japan a hundred years ago, the etiology of which was never determined. Uraguchi (1971) analyzed the records of cases of the disease called acute cardiac beriberi (Shoshinkakke) and concluded that the ailment was probably a human mycotoxicosis.

Acute cardiac beriberi was associated with the consumption of polished rice and was initially thought to be an avitaminosis. In 1910, however, the Japanese government took action to exclude mouldy rice from the markets and the incidence of acute cardiac beriberi dropped dramatically.

Uraguchi (1971) suggested that acute cardiac beriberi may have resulted from eating "yellowed rice" Such a foodstuff became pigmented and toxic to rats, and produced symptoms similar to those observed in humans affected with beriberi.

Penicillium sp.
phialide conidia conidiophore


Toxin producing fungi: Penicillium islandicum (Luteoskyrin and cyclochlorotine), P. citreoviride (citreoviridin), P. rugulosum (Rugutosin) and citrinum (citrinin).


The empirical formula of citreoviridin is C23 H30 O6. It contains one methoxy group and double bonds.

Clinical Symptoms

The clinical manifestations of acute cardiac beriberi, begin with palpitation, precordial distress, and tachypnea; fallowed by nausea and vomitting, and difficult breathing.

Within a few days, the patient suffers severe anguish, pain, severe restlessness, or sometimes violent mania. The right heart is dilated, heart sounds are abnormal, blood pressure is low, and pulse is rapid, sometimes exceeding 120 beats/min, and the patient faints.

The dyspnea increases, the skin of the extremities becames cold, dry, and cyanotic, and the voice becames husky, Finally the pulse becames feeble, the pupils dilated, consciousness is lost, and respiration fails.




In 1957 to 1958, an unusual chronic disease of the kidney occurred endemically in Yugoslavia, Rumania, and Bulgaria with a prevalence of 3-8 percent, mainly in rural areas where food is home grown. It was common in 30-50 year- old - females. In Yugoslavia, 6.5 percent of blood samples contained ochratoxin A at concentrations between 3 and 5 mg/g serum (Hurt et a/, 1982).

Barnes (1967) suggested that plant toxins or mycotoxins may be an environmental factor causing this human disease. Krogh et al, (1974) presented preliminary evidence to associate the human disease with ingestion of ochratoxin A (OTA).

This nephrotoxic compound occurs in feeds and foodstuffs and is considered a major determinant of porcine nephropathy, a form of kidney damage strikingly similar to that seen in Balkan nephropathy cases.

Renal porcine nephropathy has been reported regulary from Denmark since 1928. The law in Denmark requires that all abnormal gross appearance of kidneys must be analysed for OTA and the toxin concentration exceeds 10 g/g which corresponds to 50 g/ml in the blood, the entire carcass is condemned. Nephropathy has also been reported in chickens.


Toxin-producing fungi: Aspergillus ochraceous and Penicillium viridicatum


Ochratoxin is a dihydroisocoumarin derivative produced by seven species of Penicillium and six species of Aspergillus including A. ochraceous.

Clinical Symptoms

The disease is of indefinite onset without acute manifestations. Among the earliest and most frequent complaints are headache, lassitude, easy fatigue, and anorexia.

The typical syndrome includes a shallow, coppercolored skin, yellowing of the palms and soles, anemia in the preazotemic stage, and perhaps occasional profuse intermitent hematuria, due to tumors of the urinary passages; there is no hypertension or edema.

It becomes evident that in the endemic villages, when a high incidence of urinary tract tumors pallalles the EN occurrence and both diseases follow a similar pattern of geographic clustering, age an a sex distribution (Chernozemsky et al, 1977).




Historically, the aflatoxins were discovered as a consequence to the death of 100,000 of turkey poults ("Turkey X disease"), ducklings and chicks in England in 1960 with a loss of at least several hundred thousand dollars. The problem was eventually traced to feed contamination, specifically a shipment of Brazilian peanut meal used as poultry feed produced by Old Cake Mills, Ltd. in London. This meal, termed Rosetti meal (from the name of the ship in which it was imported), proved to be both toxic and carcinogenic and was found to be contaminated with the common fungus, Aspergillus flavus.

The active principles were extracted and isolated from A. flavus cultures by a group in England and the Netherlands (Van der Zijden. et al, 1962; Nesbitt et al, 1962), chemically identified by a research group in the U.S. (Asao et al, 1963), and named aflatoxin the "a" from Aspergillus and the "fla" from flavus.

The aflatoxins are a group of secondary fungal metabolises which have been epidemiologically implicated as environmental toxin and carcinogens in man. They are substituted coumarins containing a fused dihydrofurofuran moiety. There are four primary aflatoxins, named B1, B2, G1 and G2, from their blue and green fluorescence, respectively, on thin-layer chromatographic plates. As was generally known to be the case with aflatoxin toxicity and carcinogenicity, a similar potency series, namely AFB1 > AFB2 > AFG1 > AFG2 > has been established for aflatoxin - induced mutagenic activity and DNA damage.

Aflatoxin metabolises

AFM1 is a King hydroxylation of AFB1 at the 4 position. This metabolise was first detected in the milk of cows ingesting AFB1. It has also been detected in the urine of humans consuming AFB1 contaminated peanut butter. AFM1 could induce typical bile duct hyperplasia in day - old ducklings characteristic of AFB1.

This hemiacetal AFB2a metabolise is produced by hepatic microsome from AFB1 by hydration of the 2, 3 vinyl ether double bond resulting in hydroxylation at the 2 position.

It is possible that AFB2a plays an important role in aflatoxin acute toxicity by binding and inhibiting key enzymes of intermediary metabolism and resulting in liver cell necrosis.

AFP1 is produced by the O-demethylation of AFB1 and was the major excretory product in the urine of AFB1 -treated rhesus monkeys, where it was present as glucoronide and sulfate conjugates. It is formed in vitro by human microsomes. AFP1 was nontoxic to chicken embryos and nonmutagenic.

AFQ1 is formed from AFB1 by ring hydroxylation of the carbon atom to the carbonyl function of the cyclopentenone ring. It represents one-third to one- half of the metabolises produced from AFB1 by monkey and human liver microsomes. This methabolite is nontoxic and only 1-2% is mutagenic as AFB1 in Ames assay.

Reduction of the cyclopentenone carbonyl function of AFB1 to hydroxy group by an NADPH dependent cytoplasmic enzyme produced AFL. The toxicity of AFL is only 1/18 that of AFB1 in one day - old duckling bile duct hypenplasia assay.

AFLH was formed from AFB1, using both the microsomes and soluble enzyme preparation from human liver. (Salhab and Hisch, 1975). The compound is a dihydoxyl derivative of AFB1, with substitutions at a cyclopentenone carbonyl function and the,B carbon. It was not toxic to the chicken embryo test.


Aflatoxin and Acute Poisoning

1. Taiwan Outbreak

In 1967, there was an outbreak of apparent poisoning of 26 persons in two Taiwan rural villages (Ling et al, 1967). The victims had consumed moldy rice for up to 3 weeks; they developed edema of the legs and feet, abdominal pain, vomiting, and palpable livers, but no fever. The three fatal cases were children between 4 and 8 years. Autopsies were not done, and the caused of death could not be established. In a retrospective analysis of the outbreak, a few rice samples from affected households were assayed for aflatoxins. Two of the samples contained up to 200 ppb aflatoxin B1.

2. Kenya Case

In 1982, an acute hepatitis was reported in Kenya. There were 12 of 20 cases who died with malaise, abdominal discomfort, with subseguent appearance of dark urine and jaundice. Local dogs who shared the food were affected, with many deaths. Stored grain appeared to be the cause of the outbreak. Aflatoxin was detected in two liver samples (39 and 89 ppb). Histologically, there was centrolobuiar necrosis.

3. Uganda Case

Aflatoxin B1 was circumstantially associated with the death of a 15-year-old African boy in Uganda (Serch - Hanssen, 1970). The youth, his younger brother, and his sister became ill at the same time; the young sibling survived, but the older boy died 6 days later with symptoms resembling the victims in the Taiwan outbreak.

An autopsy revealed pulmonary edema, flabby heart. and diffuse necrosis of the liver. Histology demonstrated centrolobular necrosis with a mild fatty liver, in addition to the edema and congestion in the lungs.

A sample of the cassava eaten by these children contained 1.7 ppm aflatoxin which Alpert and Serck Hanssen (1970) suggest may be lethal if such a diet is consumed over a few weeks. This estimate is based on the acute toxicity of aflatoxin B1 in monkeys.

4. Reye's Syndrome

Reye's syndrome is an acute and often fatal childhood illness which is characterized by encephalopathy and fatty degeneration of viscera (EFDV). This syndrome was first described between 1951 and 1962 in Austraria by Reye et al.

Clinically, the main features of this syndrome are vomiting, convulsions and coma. Hypoglycemia, hypogly, corrhachia and elevated serum transaminases are the most constant biochemical abnormalities. Fatty degeneration in the liver and kidneys, and cerebral edema are the major autopsy findings.

Thailand case

As reported by Bourgeois et al (1971), a 3-year-old Thai boy was brought to a Northeast provincial hospital after a 12-hr illness of fever, vomiting, coma and convulsions. The child died 6 hours later, and an autopsy revealed marked cerebral with neuronal degeneration, severe fatty metamorphosis of the liver, kidneys, and heart, and Iymphocytolysis in the spleen, thymus, and Iymphnodes.

Upon admission of the child to the hospital, a medical team travelled to the boy's home and obtained a small sample of steamed glutinous rice which had been cooked 2 days before the onset of the child's illness and reportedly has been the only food the family had for the past 2 days. The small size of the sample precluded an accurate measurement of the amount of aflatoxins present but clinical assay indicated the amount was in the parts per million range. The rice examined also contained toxigenic strains of A. flavus, A. clavatus, A. ochraceous, and A. niger, (as shown in Table 1, Angsubhakorn et al, 1978).

Table 1: Toxins which may have caused death in a boy with Reye's syndrome in the village of Baan Kota, Khonkaen Province, Thailand.

Fungi isolated Toxins produced LD50( in rat Organs involed
A. clavatus Kotanin
Desmethyl Kotanin
Cytochalasin E 0.98 Brain-edema
(1 day-Old)  
Tryptoquivaline Tremorgen
Tryptoquivalone Tremorgen
A. niger Malciformin G. 0.9 (newborn)
(28 day-old)
A. ochraceous Ochratoxin A. 22 Renal tubular necrosis
A. flavus Aflatoxin B1 7.2 (weanling) Hepatic periportal necrosis

The B. form was found in one or more autopsy specimens from 22 of the 23 Reye's syndrome cases (Shank et at, 1971) and in several instances, these aflatoxin concentrations were as high as those seen in specimens from monkeys poisoned with the aflatoxins (Bourgeois, et al, 1971) (Table 2).

Table 2: Comparison of aflatoxin B1 concentration in autopsy specimens from Reye's syndromecases and experimetal monkeys poisoned with aflatoxin B1.

Specimen Aflatoxin B1 concentrations (g/kg specimen or ml fulid)
Human* Monkey (AFB1
Brain 1-4 30 (40 5)
Liver 93 163(40.5)
Kidney 1-4 87(40.5)
Bile 8 163(40.5)
Stool 123
Stomach content 127
Intestinal content 81

The trace amounts of aflatoxins in tissue specimens from control cases is thought to reflect chronic low-level ingestion of the mycotoxin in that area of Thailand.

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