trichothecenes and aflatoxins
These toxins are not involved in the central metabolic processes of the organism, such as the generation of energy for it to use, the formation of the building blocks of proteins, nucleic acids, and cell membranes, and are known as secondary metabolites. Secondary metabolites are found amongst the fungi and plants and include compounds such as antibiotics (e.g., penicillin, streptomycin), dyes such as indigo, flavoring and odor compounds such as menthol and limonene and even substances such as taxol (for treatment of ovarian cancer) and cyclosporin A (an immunosuppressant used to prevent transplant rejection).
Disease of cereals known as "scab" had first been characterized in the 19th Century. The diseases were caused mainly by fungi of the genus Fusarium (also known as Gibberella depending upon its mode of reproduction) and feed contaminated with scabbed grains had been found to have adverse effects on horses.
Beginning in the early 20th Century, mysterious poisonings affecting livestock, fish, and people in which fungal contamination played a previously unknown role were studied in more detail. The first such outbreak occurred in Russia in 1891, but one of the earliest to be thoroughly investigated occurred in Europe in 1928 when a widely spread poisoning among pigs was found to be due to a shipment of contaminated rye from the United States. Whatever caused the poisoning was much more toxic than previously known fungal poisons and it may have come from one several species of yeasts or fungi found in the rye. Contamination with one of the fungi the Soviets had identified, a species of Fusarium, also played a role in a large-scale poisoning by spoiled rice in the suburbs of Tokyo in 1955. The Japanese isolated a number of fungi from the contaminated rice and identified two of them as making the as yet uncharacterized toxin. Several further outbreaks of this poisoning in post-World War II Japan were associated with contamination of wheat or rice with Fusarium graminearum although it was not possible to identify the toxin or to prove that the fungus was the source.
The toxin involved had consistent symptoms:
These effects were similar to those seen in radiation poisoning meaning that the compound was called a radiomimetic and doctors will often described the symptoms of such a case as radiomimetic. By monitoring test animals for radiomimetic symptoms as they tested various fractions on them, the first of the trichothecene mycotoxins, nivalenol, was isolated from cultures of a highly toxic strain of Fusarium nivale. Subsequently, over 150 chemically related toxic compounds, including T-2 toxin have been identified in Fusarium and related species.
Stachybotrotoxicosis also arose in the Soviet Union. The first outbreak was reported in 1931 when a number of horses were affected by a syndrome that typically began with an irritation of the mouth, throat, nose and lips accompanied by swollen glands that often progressed to death. Necropsies showed extensive internal hemorrhaging, especially on the digestive tract, but with all major organs affected. These symptoms were typical of small intakes of contaminated feed. At higher levels of intake the atypical form of the syndrome was found with the symptoms are more neurological with little or no hemorrhaging.
|Typical Form||Atypical Form|
Usually lasts 8-12 days.
Irritation of mouth, throat, nose, and lips.
Swelling and soreness of glands.
Lasts 15-20 days
Similar to stage with gradual development of leukopenia (loss of white blood cells).
Lasts 1-6 days with death common.
Necrotic ulcers on nose and throat
Loss of white blood cells continues with the granulocytes becoming particularly scarce
Fresh necrotic tissues appearing in and around the mouth.
The syndrome was not transmissible, indicating a poisoning and it was eventually traced to hay contaminated with the fungus Stachybotrys chartarum. In some cases the hay used to feed horses was black with the mould. The fungus produces a number of toxic compounds of which satratoxin H is the most abundant.
In recent years, Stachybotrotoxicosis has become recognized as a public health concern in the United States. This was first brought to public notice in the 1990's when cases of young children with bleeding in the lungs (pediatric pulmonary hemosiderosis) began appearing in Cleveland, Ohio. In the past five years, the disease has claimed the lives of several children less than a year old. Their homes had been flooded and Stachybotris thrives in damp conditions, even growing on wallboard. The idea that this may have been due to Stachybotrys has been challenged.
It is arguably the law of unintended consequences that led to the discovery of aflatoxins. Peanut meal began to be incorporated into animal feed as a protein sources in the 1940's. Veterinarians in the Southern US began seeing cases of a noninfectious liver disorder in pigs, cattle, and dogs. Including a particularly devastating outbreak in a hunting dog kennel. The diseases were all associated with some form of feed contaminated with fungi, but only the dog outbreak was directly associated with peanut meal. The first documented outbreak of what we now know of aflatoxicosis occurred in a guinea pig colony in England in 1957.
The first appearance of aflatoxins is often dated to a shipment of contaminated groundnut (peanut) meal delivered to Britain from Brazil in 1959. The meal was used in poultry feed that killed turkeys, ducklings and game birds (pheasant and partridge). The syndrome was called "Turkey X disease" and was characterized by extensive liver damage including fatty change and subcutaneous hemorrhage. Further imports of contaminated meal killed calves and pigs in Britain. Contaminated cottonseed meal causing liver cancer in farm-raised trout was found to be due to the same agent. Reexamination of these earlier cases and a number of mass kills of livestock, especially of farmed fish in the US in earlier years suggested that the same agent had played a role there too.
Using the toxicity to ducklings to monitor purification, the toxin was obtained from Aspergillus flavus found in groundnuts from Uganda and was dubbed an aflatoxin.
There are fewer aflatoxins (about 10) than trichothecenes, all based on the same core chemical structure and further divided into three groups:
Although trichothecenes and aflatoxins are the best known of the mycotoxins, and those with the greatest weapons potential, they are not the only ones that are of concern, especially in agriculture. A number of other fungal toxins sicken and kill livestock every year and make meat or grains unfit for consumption. These other groups include:
Reports of chemical weapons by Soviet-backed forces first came from Cambodia (now Kampuchea) and Laos, beginning in the early 1970's and persisting into the early 1980's. Refugees reported being doused with a yellow mist from helicopters or aircraft that caused symptoms including blistering, vomiting and bloody diarrhea. The symptoms could have been caused by a chemical warfare agent such as mustard gas, indicating a serious escalation of the fighting in these areas. If the Soviets were supplying such weapons, it may have shown that they were breaking a number of treaties and could have been damaging to them. Plant samples taken from areas where attacks had taken place showed the presence of unusual mixtures of trichothecene mycotoxins, often in combination with unusual mixtures of pollen grains, but without evidence of Fusarium infection. At least one sample included traces of an industrial chemical, polyethylene glycol, that is used as a plasticizing agent and not found in nature.
When accusations were made, they were immediately countered with a number of objections.
Certainly, the reports from Laotian refugees were few (less than 200, perhaps as few as 40) and a thorough epidemiological investigation of illnesses reported by refugees had not been carried out. The interviews were not conducted in any rigorous manner and refugees were describing events that would have been well outside their normal experiences and that could have been explained in a number of ways. The best-known alternative explanation is that some of the reports of yellow rain were actually as a result of bees cleaning their hives.
There were still some problems, notably that some of the pollen was from plants not found in Indo-China, and the presence of synthetic chemicals like polyethylene glycol. Another was that trichothecenes are only manufactured at low temperatures (lower than 10°C (50°F)) that are not normally found in Indo-China. Subsequently, defectors from Laos and Vietnam admitted to the use of some forms of chemical weapons as did some Soviet prisoners of war taken in Afghanistan.
Reports from Afghanistan and Laos were similar, especially as far as symptoms were concerned. An important difference was that Afghan refugees also reported mists of other colors, including red, green and even purple that stained the ground when they settled. Afghan refugees still referred to yellow rain and some believe that careless reporters contaminated the evidence by asking leading questions about yellow rain before trained personnel could ask non-leading questions. Part of the problem in the whole story appears to have been journalists forgetting their training and another was using people who did not have the right training.
Certainly, some forms of chemical and biological weapons seemed to have been used in Afghanistan. In addition to continuing yellow rain stories, there were reports of an agent that caused bodies to rot very rapidly. This may have been a psychological weapon as Muslims are taught that the bodies of those killed in a holy war do not decay. A highly effective, and non-lethal anesthetic gas was also reported. The Soviets were later to admit to the use of one biological agent: glanders but have not commented about mycotoxin use.
The investigations of these events had begun under the Carter administration, which had come under pressure to prove that it was not soft on Communism. The accusations were eventually to be made by the Reagan administration, which was determined to be tough on Communism. It could be said that the accusation itself was more valued than its substance and that the handling of the evidence, the investigation and the making of the accusations were mishandled.
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