Other Mycotoxins

TLC is a technique for separating mixtures of chemical compounds. This photograph is a TLC plate of an extract prepared from a mouldy cereal sample. If the cereal had been of good quality and not mouldy, few of these coloured spots would be present. It is thus concluded that most of these spots are due to chemicals (‘fungal metabolites’) produced by the growth of all the different fungal species present in this mouldy grain. However, most of these natural chemicals will probably not be toxicologically important for man, at least in our current state of knowledge.

Review articles have suggested that there may be several hundred fungal metabolites that could be classed as mycotoxins, but many of these are poorly studied, or information about their toxicity is lacking. Most of these are beyond the remit of this fact sheet. Here, a selection of a few of these that have been considered to be mycotoxins will be discussed briefly, concentrating on those that have from time to time been suspected of occurring in human food or animal feed or have appeared to be linked with a problem. In contrast to other fact sheets on this site, this one takes a much more subjective view of the subject. To study all the fungal metabolites that might end up in the food supply would be a huge task. The limited funds available for research can only be justified when there are sufficient grounds to show that the fungal compound can be present in food at the retail stage and that it has suspected toxic effects that might present a significant risk to human health.

Some examples of mycotoxins that have been reported in the literature and that the reader may come across are listed below. In general these are much less studied than the priority toxins. They include some metabolites known for many years and some recognised more recently. (The inclusion or exclusion of any particular fungal metabolite should not be regarded as an indication of its importance. In many cases this has not been established).

Aspergillus clavatus toxins

The mould A. clavatus is a soil fungus that is particularly well adapted to growing in malting barley and has the potential to produce a range of toxic products that include agroclavine (one of the ergot alkaloids), cytochalasin E and K, and several compounds of the tryptoquivaline structure (these have tremorgenic properties). It is the causative agent in ‘malt workers’ lung. While the fungus can produce many of these compounds in culture, they have not been found to any significant extent in barley. The fungus has been implicated in the intoxication of cattle consuming infected grain in a number of countries, although the toxin(s) responsible have not been identified.

Aspergillus fumigatus toxins

The A. fumigatus group of moulds occurs widely, and they are pathogens that can cause fatal diseases in birds and animals. They can also produce a range of toxic compounds that include some of the tryptoquivalines, fumigaclavines and gliotoxin. A. fumigatus is often associated with heating in mouldy grain and this can be associated with a range of different symptoms including haemorrhagic and neurological problems. The occurrence of these compounds is only likely in spoiled cereals and is thus only likely to affect animal feed.

Citreoviridin

Citreoviridin is produced by P. citreonigrum (synonyms P. citreoviride and P. toxicarium), particularly in rice after harvest. It can cause cardiac beriberi in man. Acute cardiac beriberi in Japan is now only of historical interest although P. citreonigrum and citreoviridin are still reported in other parts of Asia. The fungus is said to be favoured by the lower temperatures and shorter hours of daylight occurring in the more temperate rice growing areas. The toxin is also produced by P. ochrosalmoneum. Citreoviridin has been found in un-harvested corn in the USA. Citreoviridin is an unusual molecule consisting of a lactone ring conjugated to a furan ring, with a molecular weight of 402. It is a neurotoxin.

Lesser known Fusarium toxins

The genus Fusarium is responsible for the formation of many toxic metabolites and a number of the most important mycotoxins have been described in separate fact sheets. Those less studied ones that may be of importance for human or animal health include beauvericin, enniatin and fusaproliferin.

Gliotoxin

This toxin may be produced by Aspergillus fumigatus and limited number of other Aspergillus and Penicillium species. It is a potent immunosuppressive metabolite and brings about apoptosis in cells. Because of its effects on the immune system it may have a place in transplant surgery. There is limited evidence for its occurrence in moulded cereals. A. fumigatus is a potent pathogen which can colonise the lungs and other body tissues after ingestion of spores. There is some limited evidence that gliotoxin may be formed in situ in such circumstances.

Griseofulvin

A number of Penicillium species particularly P. griseofulvum produce griseofulvin, which has been detected in mouldy cereals, although its survival into food products does not appear to have been studied. It is strongly fungistatic and has been used for treating many fungal infections. As it stops fungal cells dividing without killing them outright, therapeutic use needs to be continued for several weeks or months. However newer drugs work better than griseofulvin.

Mycophenolic acid

This compound is produced by several species of Penicillium. It has been detected in cheese as it can be produced by some species of P. roqueforti. It has antibiotic activity against bacteria. LD₅₀ in rodents is between 500 and 2500 mg/kg bodyweight per day. Monkeys fed 150 mg/kg daily for 2 weeks developed abdominal pain, and diarrhoea with bleeding and anaemia. Mutagenic activity has been reported.

b-Nitropropionic acid

A. oryzae is used for the production of soy and other sauces. However, along with other food-borne moulds, it can produce b-nitropropionic acid. Its mode of action is apparently irreversible succinate dehydrogenase inhibition that can cause a variety of symptoms, often neurological in nature. Reports of livestock poisoning via ingestion in feed showed that ingestion of b-nitropropionic acid could produce significant toxic effects up to and including death. A. oryzae has been shown to produce this toxin in cooked sweet potato, potato and ripe banana. Ames type assays for mutagenicity showed positive responses on some strains of Salmonella. It has been implicated in food poisonings in China.

Kojic acid

Kojic acid is produced by koji, a solid culture of the koji mould fungal starter, used for centuries in oriental food fermentations. It is a commonly produced metabolite that possesses antibacterial and anti fungal activity. Few oral studies exist although toxic effects have been shown in chickens consuming 4-8 mg/kg in feed. Kojic acid is also reported to have moderate cardio toxic and cardio tonic activity. 19 of 47 A. oryzae strains tested in one study produced kojic acid. Even though it is apparent that the koji moulds, including A. oryzae, can produce kojic acid, this toxin may not be present in the fermented foods. It has been reported to occur in dried fruit such as figs.

Penicillic acid

This is a toxic antibiotic produced by several species of Penicillium and Aspergillus. It has been reported in corn and dried beans and in commercial tobacco. Penicillic acid is a hepatocarcinogen in some animal species, and has also been reported to affect the heart.

PR-toxin

A metabolite formed by P. roqueforti with an LD50 of 5.8 mg/kg (i.p.) in mice and 11 mg/kg in rats. Symptoms reported include congestion and oedema of lung, kidney and brain and degeneration and haemorrhaging in the liver and kidney. It has been reported in cheese, mouldy grains and silage.

Penitrem A

The occurrence of serious outbreaks of tremorgenic and other types of neurotoxicity in domestic animals was originally linked to a number of different Penicillium species. The toxin responsible is now considered to be penitrem A, and its major source has been shown to be P. crustosum. This fungus is now recognised as a very common species in foods and feeds. P. crustosum has also been reliably reported to produce cyclopiazonic acid and roquefortine. Penitrem A is a potent neurotoxin and death or severe brain damage has been reported in field outbreaks involving sheep, cows, horses and dogs. The symptoms of penitrem A are essentially the same as those of a range of other fungal tremorgens. The potential hazard of penitrem A to man remains unknown, while the role of penitrem A and perhaps other fungal neurotoxins in human illness or neurological disorders still awaits elucidation. P. crustosum is a ubiquitous spoilage fungus and has often been isolated from cereal and animal feed samples. It can cause spoilage of corn, processed meats, nuts, cheese and fruit. The occurrence of penitrem A in animal feeds is well documented although its occurrence in human foods remains to be assessed.

Roquefortines A, B and C

Roquefortines are produces by several moulds included some used to produce mould-ripened cheeses. P. roqueforti is an essential internal component in such cheeses such as Roquefort and Gammelost (France), Gorgonzola (Italy), Stilton (UK), Tulum (Turkey), Danish blue (Denmark) and Blauschimmelkase (Switzerland). There is no evidence that roquefortines are formed in significant levels in cheese. They occur in infected feed grain, wilted grasses or whole-crop maize silages.

Stachybotryotoxin toxins, satratoxins G and H

Effects of stachybotryotoxin/satratoxins G and H are usually seen in horses but have also been suspected in small animals, including dogs. Symptoms induced by feeding fungal cultures of Stachybotrys atra are anorexia, depression, and death.

Viomellein, vioxanthin and xanthomegnin

These compounds are produced in cereals by some Penicillium and Aspergillus species. They have been shown to co-occur with ochratoxin A and citrinin and because they can affect the kidneys, they may contribute to the overall nephrotoxic effect caused by ochratoxin A, particularly in pigs. Current analytical methods are insensitive and there is no evidence for or against their survival into human food products

Walleminols

Wallemia sebi is an interesting xerophilic mould that occurs widely in dry products including cereals, dried fish and hay. It is easily missed on standard culture medium. Fungal cultures of this fungus can be very toxic probably due to the presence of metabolites called walleminols and other compounds. The occurrence of these metabolites in materials used to produce human food is poorly studied and the possibility of significant amounts reaching the consumer has not been investigated.

‘Other’ mycotoxins

There are other mycotoxins, which may occur in animal feeds or forage, for which there is little likelihood of transfer to human foods. These fall outside the scope of this fact sheet.

What remains to be discovered?

The presence of mycotoxins is usually first noticed because of their acute effects on animals or man. During the 8^th to 16th centuries the occurrence of Holy fire or St. Anthony’s fire, symptoms of which were gangrene, burning sensations and hallucinations was recognised as being caused by ergot in rye consumed by the population. Aflatoxins were discovered because of their devastating effect on turkey poults and other birds just prior to Christmas in 1960, while ochratoxin A was found as a natural component of cereals, and revealed as a major causal agent in nephropathy in pigs with possible implication in Balkan Endemic Nephropathy. Mouldy maize was recognised as a cause of disease and death in horses as long as 150 years ago and was subsequently associated with the presence of Fusarium moniliforme. But the mycotoxins responsible, the fumonisins, were not characterised until the 1980’s. It is intriguing that the main concern for human health from aflatoxins, ochratoxin A and fumonisins in developed countries is now their carcinogenic, genotoxic or immunological properties rather than the acute effects that led to their discovery.

Unless a mycotoxin exhibits clear acute effects these important chronic properties may never be suspected. This raises the question of whether further important mycotoxins remain to be discovered.

A final thought

Food safety is now of prime importance within Europe so that toxic food contaminants reaching the Consumer are minimised wherever possible. It is sobering to consider that those Nations whose food supply is most prone to mycotoxin contamination are frequently those with the least resources to tackle the problem. For many people in the developing areas of the world the priority is the immediate prevention of starvation rather than the consideration of any longer-term illness.

Selected references giving lists of other mycotoxins and fungal metabolites

BOTTALICO, A and LOGRIECO, A., 1998, Toxigenic Alternaria species of economic importance. In: Mycotoxins in Agriculture and Food Safety, edited by K. K. Sinha and D. Bhatnagar (New York: Marcel Dekker Inc., pages 65-108.

FRISVAD, J.C. and THRANE, U., 2000. Mycotoxin production by common filamentous fungi. In: Introduction to food and airborn fungi, edited by R.A. Samson and E.S Hoekstra (sixth edition, Centraalbureau voor schimmelcultures, Utrecht), pages 321-332.

FRISVAD, J. C., and SAMSON, R. A., 1991, Mycotoxins produced by species of Penicillium and Aspergillus occurring in cereals. In: Cereal grain. Mycotoxins, fungi and quality in drying and storage, edited by J. Chelkowski (Amsterdam: Elsevier), pages. 441-476.

SMITH, M. E., LEWIS, C. W., ANDERSON, J. G., and SOLOMONS, G. L., 1994, A literature review carried out on behalf of the Agro-industrial division, E2, of the European Commission Directorate-General XII for scientific research and development. Mycotoxins in Human Nutrition and Health, Chapter 1, Mycotoxins, occurrence and toxicity. Pages 1-48.

WATSON, D. H., 1985, Toxic Fungal Metabolites in Food. CRC Critical Reviews in Food Science and Nutrition, 22, 177-198.