A Concise History of Mycotoxin Research - Journal of Agricultural

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Short history of mycotoxin research John I. Pitt, and J. David Miller J. Agric. Food Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jafc.6b04494 • Publication Date (Web): 14 Dec 2016 Downloaded from http://pubs.acs.org on December 15, 2016

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Journal of Agricultural and Food Chemistry

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A CONCISE HISTORY OF MYCOTOXIN RESEARCH

10 John I. Pitt1 and J. David Miller

11 12 13 14

1

CSIRO Agriculture and Food, P.O. Box 52, North Ryde, NSW 1670, Australia.

15 16

Department of Chemistry, Carleton University

17

Ottawa, Ontario K1S5B6 Canada

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Phone: 613-520-2600 ext 1053 Fax: 613-520-3749. Email [email protected]

19 20 21 22 1

ACS Paragon Plus Environment


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ABSTRACT

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Toxigenic fungi and mycotoxins entered human food supplies about the time when mankind

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first began to cultivate crops and to store them from one season to the next, perhaps 10,000

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years ago. The storage of cereals probably initiated the transition by mankind from hunter

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gatherer to cultivator, at the same time providing a vast new ecological niche for fungi

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pathogenic on grain crops or saprophytic on harvested grain, many of which produced

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mycotoxins. Grains have always been the major source of mycotoxins in the diet of man and

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his domestic animals. In the historical context, ergotism from Claviceps purpurea in rye has

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been known probably for more than 2,000 years, and caused the deaths of many thousands of

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people in Europe in the last millennium. Known in Japan since the 17th Century, acute cardiac

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beriberi associated with the consumption of moldy rice was found to be due citreoviridin

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produced by Penicillium citreonigrum. This toxin was believed to be only of historic

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importance until its reemergence in Brazil a few years ago. Other Penicillium toxins,

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including ochratoxin A, once considered to be a possible cause of Balkan endemic

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nephropathy, are treated in a historical context. The role of Fusarium toxins in human and

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animal health, especially T-2 toxin in alimentary toxic aleukia in Russia in the 1940s, and

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fumonisins in equine leucoencephalomalasia, is set out in some detail. Finally, this paper

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documents the story of the research that led to our current understanding of the formation of

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aflatoxins in grains and nuts, due to the growth of Aspergillus flavus, and its role, in synergy

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with hepatitis B virus, in human liver cancer. During a period of climate change and greatly

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reduced crop diversity on a global basis, researchers tasked with monitoring the food system

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need to be aware of fungal toxins that might have been rare in their working careers that can

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reappear.

47 48 49

KEYWORDS: mycotoxin, history, ergotism, cardiac beriberi, ochratoxin, deoxynivalenol,

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alimentary toxic aleukia, fumonisin

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INTRODUCTION

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Essentially all of the agriculturally important fungal toxins were first recognized as animal

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diseases and often there was a long journey before their significance in humans was

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adequately understood. In most cases, the idea that fungal toxins were important was

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discounted. Mycotoxins have always been “black swans”. Romans assumed that black Swans

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did not exist, something that would have surprised the Maori and Australian aboriginal

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peoples. For >1500 years, the black swan existed in the European imagination as a metaphor

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for that which could not exist. The term black swan has come to signify the role of high-

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impact, hard-to-predict, and rare events that are beyond the realm of normal expectations

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and the psychological biases that make people individually and collectively blind to

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uncertainty.

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In the second decade of the 21st Century, it is relatively easy to identify the principal

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mycotoxins that affect food and feed. The use of next generation sequencing combined with

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alpha taxonomy and reliable sequence databases inform our perspective on the presence of

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fungi on crops. The genes responsible for the agriculturally-important mycotoxins have been

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identified in full or in part and thus their presence can be rapidly assessed in new species.

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For example, this led to the understanding that, although first thought to be confined to a

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number of species of Fusarium, some fumonsins can be produced by Aspergillus niger. FB2

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and FB4 have been found in raisins and other dried fruits and in wine 1. Untargeted analytical

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methods allow samples to be retrospectively analyzed for unanticipated fungal toxins in

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samples 2. In consequence, the focus of modern researchers is primarily on the management 3



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of known compounds emerging or re-emerging in new parts of the world because of climate

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variability and changes in agronomic practices 3. In addition, genetic change in the principal

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toxigenic fungi including F. graminearum and Aspergillus flavus is an increasing threat 3-5.

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The principal small grains, wheat, barley and rye arose from North Africa and the

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near east 6. This enabled the appearance of the first agricultural settlements around 9000 BC

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along the fertile crescent between the Euphrates and Tigris Rivers 7. Thus began the two

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important drivers of mycotoxin problems: the need to store crops and the movement of crops

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outside their areas of adaptation. The storage of cereals probably initiated the transition by

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mankind from hunter gatherer to cultivator, at the same time providing a vast new ecological

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niche for fungi pathogenic on grain crops or saprophytic on harvested grain – many of which

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we now know produce mycotoxins. The fact that insects and fungi grew on stored seeds was

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clearly recognized as an issue for the rulers of the larger settlements and towns. The rise of

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the Egyptian empire required good grain stores to feed cities and for famine. Passmore 8

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noted that “Joseph [was] the pioneer in famine administration, who fed the people of Egypt

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during seven lean years on grain stored through seven years of plenty.” Earthenware barrels

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used during the Minoan civilization in 2000 BC can still be seen in their ancient capital,

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Knossos, on Crete, today. The design of Roman granaries included raised floors that allowed

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aeration to keep the grains dry and cool as well as treatments for insect infestations 9 that

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would reduce the risk of fungal damage. The grain silos were built in walled enclosures,

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carefully plaster coated on the inside and whitewashed outside. In order to store the grain, the

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workers had to climb stairs to a small window near the top of the cone, carrying baskets.

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Through a little door at the bottom corn could be taken out.


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The small grains, emmer, wheat, barley and oats, were moved from the Middle East

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and the Nile Delta across Europe over a period of 10,000 years. The climate in sites of origin

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of these crops is dry but as they moved east and north, the seasons were shorter, cooler and

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damper. In the British Isles, the dominant crops in the Neolithic age were (in order) emmer,

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naked barley, spelt and wheat. By Roman times, this had changed to hulled barley, oats,

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emmer, wheat and rye 10. Rye was an important crop from the 7th Century 11 such that by the

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Middle Ages, rye became dominant, and the way was opened for ergot of rye to become a

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serious problem. Although ergot is mentioned in the Old Testament and during Roman times,

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epidemics of ergotism were reported in Western Europe only from about 800 AD. 12 The

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toxicity associated with ergot sclerotia in bread was not proven until 1630 1 after which

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efforts were made to promote the sieving of sclerotia from grain used for bread making. The

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first pure ergot alkaloid was not reported for another 250 years. 13

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Wheat became more important through the 17th and 18th centuries. Cullen 14 noted

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that "Wheat is the farinaceous food most generally used by the better sort of people over the

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whole of Europe, excepting the very northern parts in which it cannot be produced; but even

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there it is imported for the use of persons of condition. It has this advantage, that it can be

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formed into a more perfect kind of bread than any other of the Cerealia ..." Mortality rates in

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England declined in the second half of the 18th Century. Based on a careful study of

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population data from that period, Matossian 15 has suggested that this decline coincided with

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the change from a rye-based diet to a wheat-based diet. The disease known then as 'slow

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nervous fever', which exhibits the symptoms of ergotism, declined in importance as the 18th

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Century progressed. The sharp upsurge in human population which began at about 1750, due 5



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to reduced mortality, may well have resulted from a change in diet from rye to wheat - not

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because of nutritional factors, but because of a reduction in the ingestion of a potent

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mycotoxin.

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A more modern example of dietary shifts has been seen in Africa. In 1948, few

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African people obtained their carbohydrate calories from corn. 16 Calories came from starch

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from cassava, sorghum and millet, which are much less prone to aflatoxin contamination. 17

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At that time, peanuts were the most important source of aflatoxin. The massive increase in

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corn production in Africa in the past 50 years has resulted in greatly increased exposure to

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aflatoxin, as well as fumonisin, in many African diets. 18

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Against this background, it might be considered a mystery that the term

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“mycotoxicosis” was first used just over six decades ago. 19 The center of opinion in the food

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science world was that “there is very little evidence that moldy food causes illness”. 20

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Mycotoxins were defined 21 as “fungal metabolites which when ingested, inhaled or absorbed

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through the skin cause lowered performance, sickness or death in man or domestic animals,

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including birds.”. By convention, this excludes mushroom toxins and compounds only toxic

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to lower animals such as insects, or microorganisms. 21-23

134 135

ERGOTISM

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The association of one human illness with a fungus has been known for a long time, probably

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even by the Greeks and Romans. There are clear references to ergotism from the Middle


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Ages mainly in France but throughout continental Europe, the UK, Scandinavia and Russia.

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24

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Following the increased use of rye in central Europe in the Middle Ages, outbreaks of

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fatal ergotism were common. Although the secondary literature suggests that epidemics

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involved tens of thousands of people, this appears to be confusion with bubonic plague.

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However, documented examples of villages and surrounding areas with 100-1000 deaths in

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the period 900-1800 AD are found throughout the literature.24 These regions also

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experienced reduced fertility in villages were common. This has been attributed to the

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reproductive toxicity of sub-lethal exposure to ergot.15,24 The great mycologist Louis

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Tulasne recognized ergot sclerotia as the result of infection by the fungus Claviceps

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purpurea.25 During milling, ergot sclerotia are not readily separated from sound grain, but

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become fragmented and dispersed throughout the flour.

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The earliest reports of ergotism described two types: convulsive ergotism and

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gangrenous ergotism. The former “seized upon men with a twitching and kind of numbness

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in the hands and feet, sometimes on one side, and sometimes on both. Hence a convulsion

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invaded men on a sudden when they were about their daily employments, and first the fingers

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and toes were troubled, which convulsion afterwards came to the arms, knees, shoulders,

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hips, and indeed the whole body, until the sick would lie down, and roll up their bodies round

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like a ball, or else stretch out themselves straight at length. Terrible pains and visions

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accompanied this evil, and great clamours and screeching did the sick make”. Gangrenous

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ergot was described as “a plague of invisible fire broke out, cutting off limbs from the body

7



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and consuming many in a single night. The cries of those in pain and the shedding of burned

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up limbs alike excited pity; the stench of rotten flesh was unbearable”.24, 26

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In 1630, Dr. Thuillier, the physician to the then Prime Minister of France, the Duke of Sully,

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was the first to prove that consumption of ergoty rye caused ergotism. He observed that the

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intensity of the malady was in proportion to the amount of ergoty grain consumed and that

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people with more diverse diets suffered less. He fed ergot sclerotia to a variety of domestic

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animals and they all died. This led to a recommendation to the King and Clergy to advocate

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removal of the sclerotia by sieving. More than a Century after this, L'Abbé Tessier proposed

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cultivation of potatoes instead of rye, improved soil drainage and the enforced cleaning of

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grains. 1 Removing sclerotia from grain was promoted from the 17th Century but often

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remained ineffective well into the 20th Century in Europe. 15, 24, 27 Sieving the scleroria from

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small grains in the USA and Canada was enforced in grain quality standards from the turn of

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the 20th Century. As noted, the first structures of ergot alkaloids were reported in the 19th

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Century and are derivatives of lysergic acid.13 The mechanism of action of ergot alkaloids is

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now well understood and some are used pharmaceutically.

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The last reported outbreak of ergotism in Europe that affected consumers occurred in

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the French village of Pont St Esprit in 1954. “Bread of madness” was sold to many in the

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town 28. This resulted in more than 200 people becoming ill and four died from

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cardiovascular collapse 29, 30. More recently, occupational exposures to ergot during milling

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have resulted in severe toxicosis of the miller. 31 In the last decade, ergot has become more


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common in parts of Europe 32 and North America 33 and preventing contamination, especially

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in animal feed will require vigilance.

183 184

PENICILLIUM TOXINS IN RICE

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Cardiac beriberi. “Heart-attacking paralysis”, also known as acute cardiac beriberi was

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reported in a number of areas from the 17th centuries. Apparently this was a quite common

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disease in Japan, beginning in the second half of the 19th Century and continuing into the 20th

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Century 34 and was notable for primarily affecting young healthy males. 35 The first

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symptoms of cardiac beriberi are heart distress and palpitation, with rapid breathing. After a

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few hours, breathing becomes labored, nausea and vomiting are experienced, and within 2-3

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days, anguish, pain, restlessness and unusual behavior occur. In extreme cases, progressive

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paralysis leading to respiratory failure may cause death.

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In 1881, Dr. Junjiro Sakaki reported toxicity studies on this type of mouldy rice.

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Using ethanol extracts, he elicited symptoms in experimental animals similar to those of this

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disease in humans, leading him to conclude that mouldy rice could cause this type of

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paralysis. As a result, in 1910, a government inspection scheme dramatically reduced the

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sale of moldy rice in Japan and the incidence of cardiac beriberi suddenly decreased. 35

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Similar observations were reported by a British doctor working in the jungles in Borneo. Dr.

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Hose 36 reported that Chinese laborers suffered from beriberi and that the rice in their bags

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often became moldy. He carried out experimental feeding studies with monkeys and

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chickens. He observed that animals exposed to the moldy rice demonstrated a lack of energy 9



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and paralytic symptoms. He thus concluded that the principal cause of beriberi in Borneo was

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the consumption of moldy rice.

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The study of acute cardiac beriberi was continued by Miyake at the Rice Utilization

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Institute in Japan. In 1937, a Penicillium species, subsequently described as P. toxicarium,

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was isolated from yellow Taiwanese rice imported into Japan. The species was later shown to

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be synonymous with the earlier species P. citreoviride. After World War II, a mycotoxin was

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isolated, characterized and named citreoviridin by Yoshimasa Hitata. 37 Using high doses of

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pure citreoviridin, the symptoms of acute cardiac beriberi were reproduced in experimental

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animals. 35 Using CF1 mice, Nishie et al. 38 showed that near lethal doses (~ 5mg/kg bw) of

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citreoviridin decreased motor activities, body temperature and had cataleptic effects.

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Intravenous lethal doses resulted in erythema and shallow breathing. Death was due to heart

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failure precipitated by respiratory arrest.

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Penicillium citreoviride was renamed P. citreonigrum, a still earlier name, by Pitt. 39

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It appears to be a very rare species even in rice 40, 41 and until very recently, cardiac beriberi

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was considered to be a historical disease. However, the disease reappeared in 2006 in

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northern Brazil, where more than 1000 cases and more than 40 deaths occurred. 42 The

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presence of P. citreonigrum and citreoviridin was confirmed. The disease occurred among

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subsistence farmers growing rice crops on recently cleared land, and it was more common in

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young healthy males. Subsequent work showed that the rice was often also contaminated by

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low levels of aflatoxin and trichothecenes, however symptoms of the disease indicated death

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from cardiac beriberi. 43

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Other yellow rice toxins in Japan. After World War II, exhaustion of food production in

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Japan forced the government to import large quantities of rice from all over the world. The

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Rice Utilization Institute was re-established as the Food Control Bureau in 1947. 37 The

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Bureau soon identified other sources of toxic yellow rice. One fungal species, identified as

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Penicillium islandicum, was found to produce the toxic chemicals luteoskyrin and

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cyclochlorotine. 37 Both were hepatotoxic, and luteoskyrin was also reported to induce

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hepatic cancer at 5 mg/kg bw, a dose that is close to half the LD50. 44 The presence of P.

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citrinum and citrinin in discolored rice also caused concern for Japanese authorities in

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postwar years. 37 Citrinin has low acute toxicity. 45 Arai and Hibino 46 reported that feeding

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male F344 rats 70 mg/kg bw of citrinin for up to 80 weeks resulted in kidney damage,

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however, no effects were seen in a 90-day study with Wistar rats fed 0.2 and 20 µg/kg bw

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citrinin per day. 47

237 238

Penicillium toxins in corn. In 1913, a Penicillium species isolated from mouldy corn in

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Nebraska was reported to produce a compound that was toxic to animals when injected at

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levels of 200 to 300 mg/kg body weight. 48 The isolate was identified as P. puberulum

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Bainier, and the toxin was named penicillic acid. These authors cited work by an Italian

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investigator, Prof. B. Gosio from 1896. He reported that a Penicillium isolated from corn was

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toxic to various laboratory animals. A compound was crystallized from liquid culture filtrate

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with the empirical formula C9H10O3, similar to the known formula for penicillic acid. Gosio’s

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work is likely the first reliable account of toxin production by a Penicillium species. In the

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end, penicillic acid is not notably toxic. 49 11



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In the major growing areas in the USA, corn was stored primarily in cribs and shelled

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just before use. 50 During the 1940s, producers began changing to harvesting systems that

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shell corn at harvest, so that by 1998, only 7% of the US corn crop was stored unshelled in

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cribs. 51 The growth of Penicillium species on corn stored on the husk was a substantial

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problem in the cribs used prior to the 1970s. 52-54 Corn damaged by Penicillium was

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associated with animal toxicosis primarily in pigs and poultry. P. viridicatum cultured on

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autoclaved corn produced the toxic naphthaquinones xanthomegnin and viomellein 55, 56 and

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citrinin. 57 Modern harvesting systems and grain storage have virtually eliminated this

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problem.

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A converse trend has been the increase in silage fed to dairy cattle. In the 1960s,

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severe toxicoses in cows (e.g. fatalities, bovine abortion and placental retention) were

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associated with the growth of Penicillium crustosum, P. roqueforti and related species in

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stored corn silage in Japan 58, 59 and in the northern USA. 3, 60 General ill-thrift in mainly in

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cows was also reported. 61-62 In North America, P. roqueforti and P. paneum isolated from

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silage produce structurally diverse metabolites including roquefortine, PR toxin, penitrem A,

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marcfortine A, B and C, andrasin A and B, patulin and mycophenolic acid. 63, 64 P. roqueforti,

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which uniquely produces PR toxin, is associated with more severe toxicosis. Festuclavine,

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produced by P. paneum, and associated with ill-thrift, is similar to the alkaloids found in cool

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season fescues colonized by endophytes which are known to cause ill-thrift in grazing

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animals. 64 This problem has reappeared in cooler dairy areas around the Great Lakes and

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eastern Canada and northeastern USA and coincided with the cultivation of short season

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hybrid corn. Much this crop is used to produce silage. In Canada, the use of ensiled corn has


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increased 120 times in the past 25 years.65 Surveys in the northeast USA report pervasive

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contamination of silage by toxins from P. roqueforti and related species. 66

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OCHRATOXIN A

272 273

Ochratoxin A (OTA, 1) was originally described as a metabolite of Aspergillus ochraceus

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from laboratory experiments on fungal toxicity in South Africa.67 OTA was not reported in

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crops until 1969. 68 In the same year, the first report of OTA from a Penicillium species was

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published. 69 Soon after, more species of Aspergillus and Penicillium were shown to produce

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OTA. In post-World War II Scandinavia, porcine nephropathy was common and was

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subsequently linked to mouldy grain, then to a fungus identified as Penicillium viridicatum. 70

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A representative isolate was shown to produce citrinin and OTA. 71 The major source of the

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toxin in Denmark in swine diets was shown to be barley, 72 and the fungus was later correctly

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identified as P. verrucosum. 73 OTA was characterized as a potent kidney toxin. 74 An OTA

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serum adduct was found to be pervasive in the blood of pigs at slaughter in the region 75, 76,

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and later in humans. 77

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Although now seldom seen, Balkan Endemic Nephropathy (BEN) was a kidney

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disease with a long history in certain parts of Bulgaria, Yugoslavia and Romania, all within

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the lower Danube basin. Whole families were affected, resulting in towns with houses

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boarded up because people could not be induced to occupy them after the mysterious deaths

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of the original inhabitants. At least one small town in Bulgaria was moved to a new

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location.78, 79 Many etiological agents were suggested including plant and fungal toxins,

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viruses, lead, uranium, and silica. 80, 81 Danish researchers strongly promoted the hypothesis

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that BEN was caused by exposure to OTA 82-85 to the exclusion of competing ideas.

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Historically, exposure to OTA was common in parts of Eastern Europe where BEN

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occurred, but it has been shown more recently that OTA is present in the blood of most

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Northern and Eastern European people, in the absence of symptoms of BEN.

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A new hypothesis arose from the discovery that symptoms similar to those of BEN

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occurred in people consuming a Chinese herbal medicine inadvertently containing the weed

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Aristolochia, which produced aristolochic acid. This is a potent renal toxicant an IARC

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Class 1 human carcinogen. 86, 87 Aristolochia was shown to occur in the region, seeding just

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before wheat harvest, and then contaminating flour used for bread making. 88, 89 Exposure to

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aristolochic acid may result in tumors with the characteristic genetic signature reported in

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some BEN patients. 90, 91 A recent analysis of the weight of evidence concluded that

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aristolochic acid is the probable cause of BEN. 92

303 304

FUSARIUM TOXINS IN CEREALS

305 306

Red mold disease – scab. Human toxicosis from consuming grain damaged by what we

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now call Fusarium Head Blight(FHB) occurred in southern Japan from about 1890.

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Symptoms, including nausea, vomiting, diarrhea, abdominal pain, fever, and throat irritation

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were also reported in humans in China and Korea. 93-95 Mycological surveys of suspect grain

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revealed infections by Fusarium graminearum and related species. In the mid-1950s, feeding

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trials with rodents using naturally contaminated grain in Japan showed the signs of toxicosis


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that we now associate with deoxynivalenol (2). 94

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Probably because the toxin associated with F. graminearum was ultimately

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discovered in Japan, the literature has tended to overlook human cases elsewhere. Tsarist

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Russia also experienced serious problems with FHB. Cases of human toxicosis associated

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with consumption of moldy grains (“intoxicating bread”) were reported in Russian literature

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abstracted in English by 1917. 96 This was described by Donuin 97: “In connection with the

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extraordinary prevalence of Fusarium roseum Lk. on cereals, it was observed that the bread

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became poisonous (inebriant bread). People who ate it suffered from weakness, vertigo,

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headache, nausea and vomition.”

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American studies on FHB were reported from the mid-19th Century. 98 By the 1920s,

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it was known that grain infected by F. graminearum was toxic especially to pigs. 96, 99

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German farmers complained about feed refusal and illness in swine after feeding grain from a

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shipment from the 1927 harvest in the USA. Researchers in German isolated a number of

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fungi from the grain, including Fusarium. Culture filtrate of the Fusarium species fed by

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gavage produced feed refusal. 100 Subsequent studies in the USA showed that damaged barley

327

resulted in emesis in pigs. 101 A water extract of barley contaminated by G. saubentii [a

328

species concept that included F. graminearum] induced emesis in pigs by gavage. 102

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Experiments conducted in the mid-1960s water and methanol extracts of cultures of F.

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graminearum resulted in toxicity in mice and pigs. 103 Using strains isolated from cereals

331

affected by FHB, Prentice et al. 104 reported an emetic principle but were unable to determine

332

its chemical structure. 105

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Deoxynivalenol. Japanese researchers solved the identity of the compound that 15



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caused feed refusal and emesis. Deoxynivalenol, 3-acetyl-DON, and 3,15-diacetyl-DON were

335

identified as metabolites of F. roseum No.117, an isolate from the 1970 epidemic in Japan.94,

336

106

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an isolate of F. graminearum from contaminated corn that had elicited emesis in pigs. 107 As

338

Japanese researchers had reported the full structure in an open meeting and in the first

339

publication, the appropriate trivial name that should be used is deoxynivalenol.94 Based on

340

the emetic response, humans are probably more sensitive to deoxynivalenol than the most

341

sensitive domestic animal, pigs. 108

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US researchers later reported a partial structure of deoxynivalenol as ‘‘vomitoxin’’ from

The full toxigenic potential of F. graminearum 109-112 and the existence of two

343

important chemotypes, one producing deoxynivalenol via 15-acetyl deoxynivalenol and the

344

other via 3-acetyl deoxynivalenol, were resolved by Canadian researchers. 113 Fusarium head

345

blight damaged grain and chronic human exposure to deoxynivalenol remains a stubborn

346

problem in much of the world. 114 However, in contrast to 30 years ago, the toxicity of this

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mycotoxin is now well understood. 95, 115, 116

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Zearalenone. Corn contaminated by F. graminearum was occasionally associated

349

with estrogenic symptoms, particularly in pigs in the 1920s. 117 An active fraction was

350

isolated from corn with a partial structure reported in 1962 118 with the full structure some

351

years later. 119, 120 Zearalenone (3) proved to be a major contaminant in corn in the USA and

352

Canada, but the problem had largely disappeared by the early 1980s. This was due to a

353

combination of warmer temperatures and the use of corn hybrids that matured earlier, both

354

factors which reduced the accumulation of zearalenone. 1

355

Zearalenone affects reproduction in female pigs at very low exposures, with a dietary


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356

no-effect level of < 250 µg/kg body weight. Nonhuman primates are also very sensitive. 121

357

Zearalenone has been implicated in several incidents of precocious pubertal changes in girls

358

in Europe from acute and chronic exposure to the toxin. 122 The available data suggest that

359

zearalenone exposure may result in reproductive effects in some parts of Europe 123, 124 and

360

China. 125

361 362

ALIMENTARY TOXIC ALEUKIA

363 364

First formally described circa 1930, a disease that came to be known alimentary toxic aleukia

365

(ATA) was associated with consuming grains contaminated by Fusarium species in many

366

parts of the former Soviet Union. It was notable in civilian populations and domestic animals

367

during World War II. This was exhaustively reviewed from primary Soviet literature from the

368

time. 126, 127 Inability to harvest crops due to labor shortages meant that crops were left in the

369

field. Food insufficiency led to consumption of food prepared with contaminated grain,

370

resulting in people reporting a burning sensation in their mouths, vomiting, weakness,

371

fatigue, and tachycardia. After a period of time, affected individuals felt better, but there was

372

a progressive leucopenia, anemia, and decreased platelet count, lowering "the resistance of

373

the body to bacterial infection." As consumption of toxic grains continued, petechial

374

hemorrhages on the upper part of the body appeared together with necrotic lesions in the

375

mouth and face. Bacterial infections were common. Patients who reached this stage almost

376

always died. 128, 129 From 1942 to 1948 this disease resulted in large scale mortalities in the

377

former Soviet Union, especially in the Orenburg district north of the Caspian Sea, but also 17



378

throughout the southern and central regions of the USSR. 126, 127 In some localities, mortality

379

was as high as 60% of those afflicted, and up to 10% of the population. 130

380

The metabolites identified by the Russian scientists were called poaefusarin from F. poae and

381

sporofusarin from F. sporotrichiodes. 128 Aware of the Soviet work, and working on

382

Fusarium contaminated grain that was acutely toxic to domestic animals, researchers at the

383

University of Wisconsin isolated T-2 toxin. 131, 132 This fungus, strain “T-2” of F.

384

sporotrichiodes, misidentified as F. tricinctum, was ultimately shown to produce a suite of

385

potent trichothecenes, among other compounds. 133 Prof. Chet Mirocha at the University of

386

Minnesota established collaboration with Soviet scientists to resolve the toxin associated with

387

ATA. He obtained a small sample of poaefusarin from early preparations, and confirmed that

388

this was T-2 toxin. 134 In animals, T-2 toxin results in hemorrhagic lesions of the mouth, nose

389

and skin. Systemic exposure results in damage to white and red blood cells. The gross

390

pathology and hematopoietic effects of ATA were recapitulated in cats. 135 The toxicity of T-

391

2 has been exhaustively studied 136, 137 and needs little comment here.

392 393

FUSARIUM KERNEL ROT, ESOPHAGEAL CANCER AND FUMONISIN

394 395

Horses. In the USA, tractors did not outnumber horses until the early 1950s. Thus the health

396

of horses on farms was carefully watched over. During the droughts in the latter part of the

397

19th and first decades of the 20th Century, hundreds of thousands of horses died from what we

398

know as equine leucoencephalomalacia or ELEM. 138 This was perhaps described by the

399

Kansas State Veterinarian Dr N.S. Mayo, 139 who wrote: “During the autumn and winter of


Page 18 of 57

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400

1890-91, reports were published in various live-stock and agricultural papers, of severe losses

401

of horses, not only in Kansas, but in adjoining States, from a new and comparatively strange

402

disease, which was called ‘blind staggers,’ ‘mad staggers,’ or simply ‘staggers,’ according to

403

the symptoms presented in different cases and the imagination of the reporter. Owing to the

404

rapidity of the disease, it was difficult to get a case to watch the progress of the disease; but

405

one case was seen in the early stages, and this one had to be studied from a safe distance, as

406

the least approach threw the animal into a frenzy of excitement.” Unsurprisingly, there were

407

several theories as to the cause, but the common term was “corn stalk” disease, as it was only

408

associated with the consumption of corn.

409

Descriptions of the symptoms of ELEM from exposure to fumonisin (5) follow the

410

pattern described by Mayo 139: “…the first thing noticed was a refusal of the feed and a desire

411

for water, while sometimes drinking was performed with difficulty. Following this would be

412

dullness and a drooping of the head and ears, partial or complete blindness, loss of

413

consciousness, delirium and death, or, in a few cases, recovery. In some cases the brain did

414

not seem as badly affected as the spinal cord, and the animal would not have good control of

415

its hind parts. Some animals would press their heads against a post or wall with considerable

416

force; others would be thrown into a frenzy by the least excitement.”. 138 On post mortem, Dr.

417

Mayo 139 reported “blood-vessels of the brain were congested. There was no bulging of any

418

portion of the brain that I could discover, but a careful manipulation would reveal a soft spot

419

toward the anterior portion of the right or left cerebral hemisphere; and in cutting into the

420

white central substance, a serous abscess would be found, in which would be floating flocculi

421

of broken-down brain substance, which presented the appearance, as one stockman said, ‘of a 19



422 423

mixture of vinegar and curdled milk’.”. ELEM was reported in many countries and ultimately the discovery of the causal

424

fungus and toxin involved researchers from the USA, Africa and Europe. An American

425

researcher first recreated the disease in horses in 1902 by feeding them mouldy corn but it

426

was not until much later that the fungus F. moniliforme (now F. verticillioides) was identified

427

as the cause. 140 Researchers in the USA, France and South Africa all attempted to identify

428

the chemical responsible for ELEM. Cases of ELEM in South Africa in 1970 led to work

429

there, where researchers noticed that aside from the brain lesions, signs of kidney damage

430

with precursors for cancer were observed. This work led to the characterization of fumonisin

431

was published in 1988. The history of that discovery including the proof that fumonisin

432

caused ELEM has been comprehensively reviewed. 141, 142,143 An often-overlooked footnote is

433

that fumonisin was reported as macrofusin by French researchers working on ELEM shortly

434

after the South African published the structure of fumonisin. 144

435

Humans. High rates of esophageal cancer were reported from the 1960s in

436

parts of South Africa where corn was a major part of the diet. 145 Many theories were put

437

forward, including alcohol consumption, micronutrient deficiency, and exposures to

438

chemicals from barrels used for storage of homemade liquor. Early on, it was noticed that the

439

disease was more common when the corn in smallholder plots showed a fungal disease

440

termed “withered end” 146 which was ultimately shown to be due to the growth of F.

441

verticillioides. 147

442 443

Before the structure of fumonisin was resolved in 1988, another compound from F. verticillioides attracted attention, the in vitro mutagen fusarin C. First reported with an


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444

incomplete structure, 148 this was shown to occur in unprocessed corn infected by F.

445

verticillioides but it was not active in a rodent model. 149

446

The idea that a fungal compound that looked like a lipid could cause cancer in animal

447

models was strongly resisted. Ultimately the mechanisms that explain the disparate toxicities

448

associated with fumonisin exposure required more than 10 years of effort. 150

449 450

AFLATOXINS: NUTS, CORN AND OTHER COMMODITIES

451 452

Turkeys and other birds. It is well known that aflatoxins were discovered following the

453

deaths of 100,000 turkey poults in England in 1960, but the story of that discovery is less

454

well known. Turkey “X” disease”, so called because it resembled a viral disease, 151 also

455

affected smaller numbers of chickens and ducklings, but the cause remained a mystery for

456

about a year following the original outbreak.

457

Dr W.P. Blount, Chief Poultry Adviser at the company where the main disease

458

outbreak occurred, wrote that investigators had tested all major bacterial toxins, 18 chemicals

459

including alkalis, arsenic and thallium, 20 agricultural chemicals, pesticides and additives,

460

and a variety of feed ingredients. 151 The implicated “Rossetti” meal was found to be highly

461

toxic, but the meal was sterile. 151, 152 The same year, a high incidence of liver disease was

462

also recorded in ducklings in Kenya. A sample of the peanut meal from the Kenyan outbreak

463

was also found to be toxic and was highly contaminated by Aspergillus flavus. The fungus

464

was identified by J.J. Elphick, at the Commonwealth Mycological Institute, Kew. 153 The

465

highly fluorescent nature of aflatoxins, as the toxic compounds soon became known, enabled 21



466

sensitive assay techniques to be developed, initially by paper chromatography 154 and then by

467

the more accurate thin layer chromatography. 155

468

The discovery of aflatoxin by British and Dutch researchers 156 might have been

469

missed had it not been for the fact that virtually all the turkeys that died were being grown

470

within 100 miles of the Port of London. Thus the source of the feed could be easily traced to

471

several cargo ships from Brazil including the S.S. Rossetti, which arrived in London on July

472

7, 1960 (Hardwick Game Farm v Suffolk Agricultural and Poultry Producers Association,

473

[1966] 1 WLR 287 per Diplock LJ).

474

In the following few years, much progress was made. This included more reliable

475

analytical methods and the discovery of the four common aflatoxins that can occur in nature

476

labelled according to their florescent color on TLC and abundances as B1 (6), B2, G1 and G2.

477

Aflatoxins were found to be acutely and chronically toxic to domestic animals, and to be

478

responsible for several of the animal disease outbreaks reported around 1960. The major

479

sources of aflatoxins were peanuts, corn, cottonseed. Aflatoxins were shown to be produced

480

by Aspergillus flavus and the closely related A. parasiticus.156 Later, more sensitive assay

481

techniques, especially HPLC, were developed and A. flavus and A. parasiticus were reliably

482

differentiated. Cole 157 argued that the toxicity reported must have been due in part to

483

cyclopiazonic acid. A re-analysis of the peanut meal from the S.S. Rossetti showed that it

484

was indeed contaminated by cyclopiazonic acid. 158

485

Humans. By the mid-1930s, it had been reported that people from areas of Africa

486

where peanut consumption was high were more likely to be diagnosed with liver cancer.

487

Similar observations were made from many parts of Africa by about 1960. 159, 160 At the same


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488

time, Dr. A.G. Oettlé, from the South African Institute for Medical Research reported a

489

groundbreaking epidemiological study of African cancer occurrence. He concluded that the

490

high rates of hepatocellular carcinoma observed in some regions of Africa could be due to the

491

newly discovered aflatoxins (or some other fungal toxin) or organisms such as parasites. 161

492

The use of peanut meal as a protein supplement for children mainly in Africa

493

commenced soon after the end of World War II, as an initiative of the newly established Food

494

and Agriculture Organization (FAO). Soon after that, aflatoxin was found to be highly toxic

495

162

496

committee of the FAO program established a provisional limit of 30 µg/kg of total aflatoxin

497

in peanut protein supplements based on carcinogenicity. 165 Ironically this limit is frequently

498

breached in African peanut butter to this day. 166, 167

499

and carcinogenic. 152, 163 FAO officials were informed 164 and in early 1966, the advisory

Quite early, the question arose, “What effects might aflatoxins have on man?” 168, 169

500

As soon as aflatoxin was discovered and a rudimentary assay had been developed, levels

501

were measured in samples of peanut products from India, Uganda and Tanganyika, French

502

West Africa, Nigeria, Gambia and Ghana. 170 In South Africa in 1963, of 501 samples tested,

503

75 contained 2,000 µg/kg or more of aflatoxin, while in Senegal, 500 samples examined over

504

2 years contained 100-20,000 µg/kg. 171 These data permitted studies on non-cancer health

505

outcomes. For example, in Senegal, a group of children less than year old each received 70-

506

140 g of peanut meal per day for 10 months as a treatment for protein energy

507

malnourishment, kwashiorkor. Most of these children suffered from liver damage. 172 The

508

meal samples were later found to be contaminated with aflatoxin at 500-1000 µg/kg,

509

providing an aflatoxin intake of 35-140 µg/day. Children in Uganda were shown to be 23



510

similarly exposed. 173 Children in India fed peanut protein supplements containing aflatoxin

511

were shown to have serious liver damage. 174 This became a widespread problem in India,

512

notably during drought years. 175

513

Among the first of the now tragically high number of child deaths resulting from high

514

exposure to aflatoxin was reported from Uganda in 1967. A 15-year-old boy died from acute

515

liver failure after consuming food containing 1,700 µg/kg aflatoxin. 176 The author suggested

516

that similar cases were at the time likely to be underdiagnosed. Since then, other cases have

517

been documented in Africa 177, 178 and Thailand, 179 among other places.

518

Epidemiological studies in Swaziland, 180 Uganda 181 and Kenya 182 showed a fairly

519

strong linkage between aflatoxin and human cancer. Studies in Thailand, 183 Kenya, 184

520

Mozambique 185 and Swaziland 186 permitted a relationship to be shown between exposures to

521

naturally occurring mixtures of aflatoxin liver cancer rates. 187 The first review of aflatoxin

522

by the International Agency for Research on Cancer in 1971 stated that “Considerable

523

evidence is now available to indicate that market sales of some food commodities in poor

524

countries often contain aflatoxins. Increased frequency of liver cancer has been recorded in

525

populations consuming diets contaminated by aflatoxins and possibly other mycotoxins but

526

no causal relationship has been established”. 188

527

However, approximately at the same time population based studies were indicating

528

that the hepatitis B virus was a cause of primary liver cancer. 189 A series of studies in

529

Senegal and other countries showed a high relative risk of seropositivity for hepatitis B and

530

primary liver cancer. 190, 191 This led to strongly held views as to whether all the cancer was

531

caused by hepatitis B and the concurrent aflatoxin exposure was coincidental. For example,


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532

an official of the FDA, Mr. Leonard Stoloff estimated aflatoxin exposure in children in rural

533

communities in the southeastern USA. He suggested that they may have ingested as much as

534

40 ng/kg body weight of aflatoxin per day, mostly from corn. 192 From previously published

535

figures, 187 such exposure level would suggest 4-10 deaths from primary liver cancer per

536

10,000 population per annum: the actual level found was about 1 case. This was less than in

537

other regions of the USA where aflatoxin ingestion was insignificant. From this, Stoloff

538

concluded in a 1982 that aflatoxin was not a cause of liver cancer. 193 However, two

539

subsequent analysis found that his assessment of aflatoxin exposure for the different regions

540

in the U.S. was flawed; actual exposures were lower. The acquisition of better data on cancer

541

potency of aflatoxin demonstrated that aflatoxin in this population in the southern States was

542

associated with a large fraction of the liver cancer burden. 194,195

543

High human exposure to other carcinogens in areas with high rates of liver cancer

544

complicated the debate for decades. The second time IARC considered aflatoxin, the panel

545

offered a similar comment to that in 1971: “The studies of liver cancer incidence in relation

546

to aflatoxin intake provide circumstantial evidence of a causal relationship.” 196 IARC first

547

classified naturally occurring mixtures of aflatoxin as class 1 carcinogens in 1987.197 With

548

the availability of high quality data on the interactions between hepatitis B and aflatoxin, 198

549

it was finally possible to clarify the interaction and affirm aflatoxin as a class 1 carcinogen in

550

1992.86, 199 In 2016, it may be hard to understand that there was a debate nearly as passionate

551

as that for smoking and cancer around aflatoxin and human carcinogenicity even as late as

552

1989. 200 However, determination of the relative risks for aflatoxin and hepatitis B required

553

sophisticated biomarkers to prevent exposure misclassification and end the debate. 201 A 25



554

further issue that delaying consensus was that, although the mechanism is not understood, 202

555

co-exposure is synergistic or supra-additive in a number of studies. 203

556 557

MYCOTOXINS IN THE DECADES AHEAD

558 559

There are some other mycotoxins not discussed here that have been found in some locations,

560

crops and environments (e.g. diacetoxyscirpenol, sterigmatocystin). However, their

561

discovery has followed the same pattern we describe above: health impacts in domestic

562

animals leading to questions of human health relevance.

563 564

Regardless, a number of factors will play a major role in shaping the field over the next

565

several decades. The first is the economic consequence of mycotoxin contamination in the

566

fully developed market and developing economies. In the USA, estimates of the cost of

567

aflatoxin associated losses at ca. $300 million in food and feed crops (per year) 204 to $50-1.7

568

billion for corn depending on weather conditions. 205 Producer losses associated with a major

569

epidemic of Fusarium head blight and deoxynvivalenol contamination in Ontario in 1996

570

were estimated at ca. $145 million.206 However, these estimate represent only part of the

571

economic losses. In bad years, there are large costs for testing through the entire value chain

572

as well as the diversion and transport of rejected lots to alternative uses if possible 207, 208 as

573

well as the cost of research. 208 Also in bad years, downgraded grain ends up being fed to

574

animals which can be associated with reduced weight gain in sensitive species. 209

575

Considering this broader perspective, a Fusarium head blight epidemic in the Midwest USA


Page 26 of 57

Page 27 of 57


576

in the period 1998-2000 was associated with $870 million in direct losses and more than

577

twice that in secondary economic losses.210

578 579

Developing countries are affected by similar economic consequences and inability to

580

export.211 Further, there is a large burden on population health mainly in Africa as well as

581

parts of Latin America and East Asia.18 One study estimated that between 25,000 and

582

155,000 cases of liver cancer due to aflatoxin alone occur across the world each year. 212

583

Using different methodology, the same authors revised this estimate to between 105,000 and

584

142,000 new cases due to aflatoxin alone per annum.213 A report from the Foodborne

585

Diseases Burden Epidemiology Reference Group of the World Health Organization 214 used

586

global estimates of incidence to calculate illnesses, deaths and disease attributable life years

587

lost (DALYs) due to dietary dioxin, aflatoxin, cyanide in cassava and peanut allergens.

588

Aflatoxin was associated with the highest global DALYs (636,869) due to liver cancer. A

589

much larger public health burden is likely to be associated with the influence of aflatoxin in

590

childhood stunting. 18

591 592

A second major factor that is shaping the research agenda for mycotoxins is the fact that that

593

over the past 50 years, diets in all countries have converged to a number of globally

594

important cereal and oil crops. There has been a corresponding decline of other cereals, oil

595

crops and starchy root species, notably in Africa. Millets, sorghum, yams, cassava, and sweet

596

potatoes have markedly declined.215 In the USA, crop diversity peaked in 1960 and is

597

currently at levels comparable to 1870.216 As noted, in Africa, there was a profound shift from 27



598

a more diverse food system prior to the 1960s to one where corn and nuts supply most

599

calories.16, 215 The crops they replaced as sources of calories, sorghum, millet, and cassava

600

generally have low concentrations of aflatoxin in Africa. 17, 217

601 602

A final issue that merits attention is exposure assessment. The above discussion of aflatoxin

603

illuminates the critical biomarker data that was needed to resolve the attributable risk for liver

604

cancer and is playing at present in a similar question about child stunting. The fully

605

developed market economies have depended on a system where exposure is assessed based

606

on a two-step process. First, mycotoxins are analyzed in crops and foods. These data are

607

gathered and, where available, statistical models based on national diet survey data to project

608

exposure across the population. Both of these steps are subject to sampling and analytical

609

uncertainties. Recent biomonitoring data for deoxynivalenol in some countries in Europe

610

have indicated that the population estimates made by the sampling/analysis/modelling

611

approach may not always be secure. A study of urinary mycotoxin biomarkers in a population

612

in Belgium indicated that 16–69% of the population possibly exceeded the tolerable daily

613

intake for deoxynivalenol.218 A similar, albeit smaller study in Italy reported that and 40% of

614

volunteers possibly exceeded the tolerable daily intake. 219 There are two possible reasons for

615

this outcome. The first is that in years where incidence of FBH and deoxynivalenol

616

contamination are high, maximum residue levels might not prevent some individuals from

617

exceeding the tolerable daily intake. 220 Another possibility is the hydrolysis of undetected

618

deoxynivalenol glucoside in cereal products affected FHB in the gut. Although first

619

recognized 30 years ago,221 in recent years, the prevalence of glycosylated deoxynivalenol in


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620

foods notably bread and beer has been extensively documented.222 Although deoxynivalenol

621

glucoside largely passes through the gut unchanged, a percentage of the population has a gut

622

microbiome with the capacity to hydrolyse the glucose to deoxynivalenol.223,224 Regardless,

623

these biomonitoring studies mainly from Europe suggest that more use should be made of

624

urinary biomarkers to assess exposure.

625 626

ACKNOWLEDGMENTS

627 628

We thank Dr. Lauren Jackson and Prof. Dojin Ryu for organizing the symposium on

629

mycotoxins at the 2016 Spring meeting of the American Chemical Society and encouraging

630

the drafting of this paper. We are grateful for the suggestions of anonymous reviewers on the

631

manuscript. We thank Agriculture Canada and Carleton University (JDM) and the CSIRO

632

(JP) for the opportunity to work on mycotoxins. We have benefited from working with some

633

of the leading figures in the history of this field over the past half Century.

634 635

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Figure 1. Structures of the agriculturally-important mycotoxins discussed: ochratoxin A, 1,

1190

deoxynivalenol, 2, zearalenone, 3, T-2 toxin, 4, fumonisin B1, 5 and aflatoxin B1, 6.

55



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A Concise History of Mycotoxin Research - Journal of Agricultural

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