Trichothecene

Chemical structure of Trichothecenes

Trichothecenes are a very large family of chemically related mycotoxins produced by various species of Fusarium, Myrothecium, Trichoderma, Trichothecium, Cephalosporium, Verticimonosporium, and Stachybotrys. Trichothecenes belong to sesquiterpene compounds. The most important structural features causing the biological activities of trichothecenes are: the 12,13-epoxy ring, the presence of hydroxyl or acetyl groups at appropriate positions on the trichothecene nucleus and the structure and position of the side-chain. They are produced on many different grains like wheat, oats or maize by various Fusarium species such as F. graminearum, F. sporotrichioides, F. poae and F. equiseti.

Some molds that produce trichothecene mycotoxins, such as Stachybotrys chartarum, can grow in damp indoor environments. It has been found that macrocyclic trichothecenes produced by Stachybotrys chartarum can become airborne and thus contribute to health problems among building occupants.[1][2] The poisonous mushroom in Japan and China, Podostroma cornu-damae contains six trichothecenes; satratoxin H, roridin E, verrucarin and others.

Toxicity mechanisms

This group of structurally related mycotoxins has a strong impact on the health of animals and humans. Trichothecenes are powerful inhibitors of protein synthesis. They do this by reacting with components of the ribosomes: the structure within the cell where proteins are made. The specific site of action of T-2 toxin, which is a reaction with a critical site on the ribosomal RNA (rRNA), is known. Protein synthesis is an essential function in all tissues, but tissues where cells are actively and rapidly growing and dividing are very susceptible to the toxins.[3] Trichothecenes are different from most other potential weapons toxins because they can act through the skin. Compared with some of the other mycotoxins such as aflatoxin, the trichothecenes do not appear to require metabolic activation to exert their biological activity. After direct dermal application or oral ingestion, the trichothecene mycotoxins can cause rapid irritation to the skin or intestinal mucosa. In cell-free systems or single cells in culture, these mycotoxins cause a rapid inhibition of protein synthesis and polyribosomal disaggregation. Thus, we can postulate that the trichothecene mycotoxins have molecular capability of direct reaction with cellular components. Despite this direct effect, it is possible to measure the toxicokinetics and the metabolism of the trichothecene mycotoxins.[4]

Regulatory issues

When it comes to animal and human food, type A trichothecenes (e.g. T-2 toxin, HT-2 toxin, diacetoxyscirpenol) are of special interest because they are more toxic than the other foodborne trichothecenes i.e. type B group (e.g. deoxynivalenol, nivalenol, 3- and 15-acetyldeoxynivalenol). However, deoxynivalenol is of concern as it is the most prevalent trichothecene in Europe.[5] The major effects of trichothecenes – related to their concentration in the commodity – are reduced feed uptake, vomiting and immuno-suppression. A relatively few countries, primarily in the European Union, have recommended maximum limits for these mycotoxins in food and animal feed. However, trichothecenes are often tested for elsewhere, in order to prevent them from entering the food chain and to prevent losses in animal production.

Occurrence and outbreaks

Trichothecenes have been reported throughout the world.[6] In modern history, incidences of emesis in animals and humans after consumption of cereals infected with Fusarium species have been described in early 1900s.[7][8] Around 100,000 people in Soviet Union died due to alimentary toxic aleukia, a disease apparently caused by consuming grains infested with Fusarium sp. which are high producers of T-2 toxin.[9] A disease of similar etiology, Akakabibyo (in case of equine, “bean-hulls poisoning”), has also been associated with trichothecene contaminated grains in Japan.[10] Cereals or their products contaminated with trichothecenes including DON, T-2 toxin, and NIV, have also been associated with outbreaks of gastrointestinal disorders in China.[11]

Trichothecenes including DON, T-2 toxin, and diacetoxyscirpenol are also important from the view of biological warfare.[12] A controversy exists as to whether the former Soviet Union and its military client states Laos and Vietnam used bioweapons containing these toxins. While the evidence is admittedly scant (20 samples in Laos for the "Yellow Rain" attacks), and some reputable laboratories report having found no toxins, other equally reputable laboratories and researchers do report having found toxins, particularly tricothecenes, for which the provenance is uncertain, with some researchers asserting natural origin from fusarium being possible, others stating that in the biome where the "Yellow Rain" attacks took place that fusarium species known to exist in the area are not known to produce toxin in vivo. Evidence studied by the United States government, its allies, and independent journalists in this connection included: • interviews of Hmong survivors of and eyewitnesses to lethal yellow rain attacks in Laos, who provided consistent descriptions of the episodes; • interrogations of a defecting Laotian Air Force officer and North Vietnamese ground troops, who corroborated the descriptions of attacks and admitted using the chemicals; • interrogations of prisoners of war who admitted being involved in attacks where unconventional weapons were used (for example, in Afghanistan); • laboratory confirmations of Soviet use of chemical agents, and • the presence of Soviet-manufactured chemical agents and Soviet technicians in Laos. The evidence supports the contention that trichothecene mycotoxins were used as biological warfare agents in Southeast Asia and Afghanistan by the former Soviet Union and its surrogates.[13]

Trichothecenes not found in the Laotian environment local to the reported attacks were found in some of the Laotian samples, in the blood of several attack survivors and in the body tissues of one deceased attack victim. Further, some of the samples of yellow samples with tricothecene also had the surfactant lauryl sulfonate mixed in with the material; Sterling Seagrave, wire-service correspondent and author of the book "Yellow Rain" speculates that admixture of surfactants with weaponized tricothecenes delivered in rainy Laos may account for the relative lack of residue.[14]

Dr. Mathhew Meselson of the Harvard Sussex biological warfare project famously stated that the "Yellow Rain" was actually fallout of pollen from mass swarms of migrating bees in the area and not a laydown of weaponized tricothecenes.[15] Meselson's "bee feces/pollen" theory, which is cited by some writers as discrediting the hypothesis that "Yellow Rain" was biological warfare activity has been called into dispute itself. The trichothecenes found in "Yellow Rain" are not known to be produced by organisms native to the biome inhabited by the Hmong villagers reporting the attacks. Perhaps more to the point, bee feces have never been reported in mass poisonings other than in "Yellow Rain" incidents.

It is perhaps relevant that at roughly the same time as the "bee-feces" paper, Dr. Meselson had repeated the former Soviet Union's claim that an anthrax outbreak at the former Sverdlovsk, USSR (now Yekaterinburg, Russia) was owing to human consumption of infected meat from a meat-packing plant the nearby town of Aramil.[16] It was not until research disclosing that human fatalities were clustered in and around Sverdlovsk itself and no meat-packing plant had ever existed in Aramil appeared in The Wall Street Journal[17] that Dr. Meselson and others published a second paper analyzing samples of the Sverdlovsk anthrax and showing they included strains known to be used in biological warfare (the second paper failed to credit The Wall Street Journal article and any role it may have played in revising Dr. Meselson's opinion).[14][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35]

Vaccine research

There is no licensed vaccine in the US to protect against trichothecene mycotoxins. They are extremely toxic with no antidote or vaccine available. T-2 mycotoxins are also the only substances used in biological warfare that can be absorbed through a person's skin.

Epoxitrichothecenes

Epoxitrichothecenes are a variation of the above, and were once explored for military use in East Germany, and possibly the whole Soviet bloc.[36] There is no feasible treatment once symptoms of epoxithichothecene poisoning set in, though the effects can subside without leaving any permanent damage.

The plans for use as a large-scale bioweapon were dropped, as the relevant epoxitrichothecenes degrade very quickly under UV light and heat, as well as chlorine exposure, making them useless for open attacks and the poisoning of water supplies.

References

  1. ↑ Detection of Airborne Stachybotrys chartarum Macrocyclic Trichothecene Mycotoxins in the Indoor Environment
  2. ↑ Etzel RA (2002). "Mycotoxins". Journal of the American Medical Association 287 (4): 425–427. doi:10.1001/jama.287.4.425. PMID 11798344.
  3. ↑ T-2 Toxin, Essential Data
  4. ↑ Trichothecene mycotoxins
  5. ↑ Miller, J. D. 2003. Aspects of the ecology of fusarium toxins in cereals. In: Mycotoxins and Food Safety. Vries, J. W. de, M. W. Trucksess, L. S. Jakson (eds.). Kluwer Academic/Plenum Publishers, New York. pp. 19-27.
  6. ↑ Dohnal V., Jezkova A., Jun D., Kuca K. (2008). "Metabolic pathways of T-2 toxin". Current Drug Metabolism 9 (1): 77–82. doi:10.2174/138920008783331176. PMID 18220574.
  7. ↑ Naumov, N. A. 1916. Intoxicating bread. Min. Yeml. (Russia), Trudy Ruiri Miwel. i. Fitopatol. Uchen, Kom. 216.
  8. ↑ Dounin, M. 1930. The fusariosis of cereal crops in European-Russia in 1923. Phytopathol. 16: 305-308.
  9. ↑ Joffe, A. Z. 1950. Toxicity of fungi on cereals overwintered in the field: on the etiology of alimentary toxic aleukia. Dissertation, Inst. Bot. Acad. Sci. Leningrad. P. 205.
  10. ↑ Ueno, Y., K. Ishii, K. Sakai, S. Kanaeda and H. Tsunoda. 1972. Toxicological approaches to the metabolites of Fusaria. IV. Microbial survey on “bean-hulls poisoning of horses” with the isolation of toxic trichothecenes, neosolaniol and T-2 toxin of Fusarium solani M-1-1. Japanese J. Exp. Med. 42: 187-203.
  11. ↑ Lou, X. Y. 1988. Fusarium toxins contamination of cereals in China. Proc. Japanese Assoc. Mycotoxicology. Suppl. 1: 97-98.
  12. ↑ Henghold II, W. B. 2004. Other biologic toxin bioweapons: Ricin, staphylococcal enterotoxin B, and trichothecene mycotoxins. Dermatologic Clinics. 22: 257-262.
  13. ↑ Robert W. Wannemacher, JR, PhD and Stanley L. Wiener, MD, Chapter 34, "Trichothecene Mycotoxins," of Medical Aspects Of Chemical And Biological Warfare, FR Sidell MD, E.T. Takafuji MD MPH, David R. Franz DVM, PhD, eds, part of the Textbook of Military Medicine series, Office of The Surgeon General, Department of the Army, United States of America.
  14. 1 2 Seagrave S. Yellow Rain: A Journey Through the Terror of Chemical Warfare. New York, NY: M Evans; 1981.
  15. ↑ Nowicke JW, Meselson M. Yellow rain—A palynological analysis. Nature. 1984;309(5965):205–207.
  16. ↑ Meselson, Matthew, Jeanne Guillemin, Martin Hugh-Jones, Alexander Langmuir, Ilona Popova, Alexi Shelokov, Olga Yampolskaya. The Sverdlovsk Anthrax Outbreak of 1979. Science: 266, 18 Nov., 1994; 1202-1208.
  17. ↑ Peter Gumbel, "The Anthrax Mystery," The Wall Street Journal, 21 October 1991
  18. ↑ Meselson M, Guillemin J, Hugh-Jones M, et al. (November 1994). "The Sverdlovsk anthrax outbreak of 1979". Science 266 (5188): 1202–8
  19. ↑ Rosen R. T., Rosen J. D. (1982). "Presence of four Fusarium mycotoxins and synthetic material in 'yellow rain'. Evidence for the use of chemical weapons in Laos". Biomed. Mass Spectrom 9 (10): 443–450. doi:10.1002/bms.1200091007. PMID 6216925.
  20. ↑ Haig AM Jr. Chemical Warfare in Southeast Asia and Afghanistan. Washington, DC: US Government Printing Office; March 22, 1982. Report to the Congress.
  21. ↑ Watson, S. A., C. J. Mirocha and A. W. Hayes. 1984. Analysis for trichothecenes in samples from southeast Asia associated with 'yellow rain'. Fundamental Appl. Toxicol. 4: 700-717.
  22. ↑ Mirocha CJ. Hazards of scientific investigation: Analysis of samples implicated in biological warfare. Journal of Toxicology-Toxin Reviews. 1982;1(1):199–203.
  23. ↑ Mirocha CJ, Pawlosky RA, Chatterjee K, Watson S, Hayes W. Analysis for Fusarium toxins in various samples implicated in biological warfare in Southeast Asia. J Assoc Off Anal Chem. 1983;66(6):1485–1499.
  24. ↑ Greenhalgh R, Miller JD, Neish GA, Schiefer HB. Toxigenic potential of some Fusarium isolates from Southeast Asia. Appl Environ Microbiol. 1985;50(2):550–552.
  25. ↑ Ricaud D. Les Recherche de Défense Contre les Armés Biologique et Chimiques. Paris, France: École Polytechique; 1983. ISBN 2-7170-0738-5.
  26. ↑ Ember LR, Sorenson WG, Lewis DM. Charges of toxic arms use by Iraq escalate. Chemical and Engineering News. 1984;62(12):16–18.
  27. ↑ Ember LR. Yellow rain. Chemical and Engineering News. 1984;62(2):8–34.
  28. ↑ Watson SA, Mirocha CJ, Hayes AW. Analysis for trichothecenes in samples from Southeast Asia associated with “Yellow Rain.” Fundam Appl Toxicol. 1984;4(5):700–717.
  29. ↑ Seeley TD, Nowicke JW, Meselson M, Guillemin J, Akratanakul P. Yellow rain. Sci Am. 1985;253(3):128–137.
  30. ↑ Dashek WV, Mayfield JE, Llewellyn GC, O’Rear CE, Bata A. Trichothecenes and yellow rain: Possible biological warfare agents. Bioessays. 1986;4(1):27–30.
  31. ↑ Yellow rain report. NBC Defense Technology International. 1986;1(2):11–12.
  32. ↑ Marshall E. The apology of yellow rain. Science. 1983;221(4608):242.
  33. ↑ Yellow rain: British analyses find no toxin. Nature. 1986;321(6069):459. News.
  34. ↑ Wannemacher RW, Bunner DL, Pace JG, Neufeld HA, Brennecke LH, Dinterman RE. Dermal toxicity of T-2 toxin in guinea pigs, rats, and cynomolgus monkeys. In: Lacey J, ed. Trichothecenes and Other Mycotoxins. Chichester, England: John Wiley & Sons Ltd; 1985: 423–432.
  35. ↑ Bunner DL, Upshall DG, Bhatti AR. Toxicology data on T-2 toxin. In: Report of Focus Officers Meeting on Mycotoxin Toxicity, September 23–24, 1985. Suffield, Alta, Canada: Defense Research Establishment at Suffield; 1985.
  36. ↑ Die Chemie der Kampfstoffe, GDR Government publishing, 1988

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