Chemistry:Aflatoxin

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Chemical structure of aflatoxin B1

Aflatoxins are poisonous carcinogens that are produced by certain molds (Aspergillus flavus and Aspergillus parasiticus) which grow in soil, decaying vegetation, hay, and grains. They are regularly found in improperly stored staple commodities such as cassava, chili peppers, corn, cotton seed, millet, peanuts, rice, sesame seeds, sorghum, sunflower seeds, tree nuts, wheat, and a variety of spices. When contaminated food is processed, aflatoxins enter the general food supply where they have been found in both pet and human foods, as well as in feedstocks for agricultural animals. Animals fed contaminated food can pass aflatoxin transformation products into eggs, milk products, and meat.[1] For example, contaminated poultry feed is suspected in the findings of high percentages of samples of aflatoxin-contaminated chicken meat and eggs in Pakistan.[2]

Children are particularly affected by aflatoxin exposure, which is associated with stunted growth,[3] delayed development,[4] liver damage, and liver cancer. An association between childhood stunting and aflatoxin exposure[5] has been reported in some studies[6][7] but could not be detected in all.[8][9] Furthermore, a causal relationship between childhood stunting and aflatoxin exposure has yet to be conclusively shown by epidemiological studies, though such investigations are underway.[10][11] Adults have a higher tolerance to exposure, but are also at risk. No animal species is immune. Aflatoxins are among the most carcinogenic substances known.[12] After entering the body, aflatoxins may be metabolized by the liver to a reactive epoxide intermediate or hydroxylated to become the less harmful aflatoxin M1.

Aflatoxins are most commonly ingested. However the most toxic type of aflatoxin, B1, can permeate through the skin.[13]

The United States Food and Drug Administration (FDA) action levels for aflatoxin present in food or feed is 20 to 300 ppb.[14] The FDA has had occasion to declare both human and pet food recalls as a precautionary measure to prevent exposure.

The term "aflatoxin" is derived from the name of one of the molds that produce it, Aspergillus flavus. It was coined around 1960 after its discovery as the source of "Turkey X disease".[15] Aflatoxins form one of the major groupings of mycotoxins.

Major types and their metabolites

At least 14 different aflatoxins are produced in nature.[16] Aflatoxin B1 is considered the most toxic and is produced by both Aspergillus flavus and Aspergillus parasiticus. Aflatoxin M1 is present in the fermentation broth of Aspergillus parasiticus, but it and aflatoxin M2 are also produced when an infected liver metabolizes aflatoxin B1 and B2.

  • Aflatoxin B1 and B2, produced by Aspergillus flavus and A. parasiticus
  • Aflatoxin G1 and G2, produced by some Group II A. flavus and Aspergillus parasiticus[17]
  • Aflatoxin M1, metabolite of aflatoxin B1 in humans and animals (exposure in ng levels may come from a mother's milk)
  • Aflatoxin M2, metabolite of aflatoxin B2 in milk of cattle fed on contaminated foods[18]
  • Aflatoxicol
  • Aflatoxin Q1 (AFQ1), major metabolite of AFB1 in in vitro liver preparations of other higher vertebrates[19]

Contamination conditions

Aspergillus fumigatus micrograph, as seen under an electron microscope

Aflatoxins are produced by both Aspergillus flavus and Aspergillus parasiticus, which are common forms of 'weedy' molds widespread in nature. The presence of those molds does not always indicate that harmful levels of aflatoxin are present, but does indicate a significant risk. The molds can colonize and contaminate food before harvest or during storage, especially following prolonged exposure to a high-humidity environment, or to stressful conditions such as drought.

The native habitat of Aspergillus is in soil, decaying vegetation, hay, and grains undergoing microbiological deterioration, but it invades all types of organic substrates whenever conditions are favorable for its growth. Favorable conditions include high moisture content (at least 7%) and high temperature. Aflatoxins have been isolated from all major cereal crops, and from sources as diverse as peanut butter and cannabis. The staple commodities regularly contaminated with aflatoxins include cassava, chilies, corn, cotton seed, millet, peanuts, rice, sorghum, sunflower seeds, tree nuts, wheat, and a variety of spices intended for human or animal consumption. Aflatoxin transformation products are sometimes found in eggs, milk products, and meat when animals are fed contaminated grains.[1]

A study conducted in Kenya and Mali found that the predominant practices for drying and storage of maize were inadequate in minimizing exposure to aflatoxins.[20]

Organic crops which are not treated with fungicides may be more susceptible to contamination with aflatoxins.[21]

Pathology

No animal species is immune to the acute toxic effects of aflatoxins. Adult humans have a high tolerance for aflatoxin exposure and rarely succumb to acute aflatoxicosis,[22] but children are particularly affected, and their exposure can lead to stunted growth and delayed development, in addition to all the symptoms mentioned below.[4]

High-level aflatoxin exposure produces an acute hepatic necrosis, resulting later in cirrhosis or carcinoma of the liver. Acute liver failure is made manifest by bleeding, edema, alteration in digestion, changes to the absorption and/or metabolism of nutrients, and mental changes and/or coma.[citation needed]

Chronic exposure increases the risk of developing liver and gallbladder [23] cancer, as aflatoxin metabolites may intercalate into DNA and alkylate the bases through epoxide moiety. This is thought to cause mutations in the p53 gene, an important gene in preventing cell cycle progression when there are DNA mutations, or signaling apoptosis (programmed cell death). These mutations seem to affect some base pair locations more than others, for example, the third base of codon 249 of the p53 gene appears to be more susceptible to aflatoxin-mediated mutations than nearby bases.[24]

Chronic, subclinical exposure does not lead to symptoms so dramatic as acute aflatoxicosis.

The expression of aflatoxin-related diseases is influenced by factors such as species, age, nutrition, sex, and the possibility of concurrent exposure to other toxins. The main target organ in mammals is the liver, so aflatoxicosis primarily is a hepatic disease. Conditions increasing the likelihood of aflatoxicosis in humans include limited availability of food, environmental conditions that favour mould growth on foodstuffs, and lack of regulatory systems for aflatoxin monitoring and control.[25]

A regular diet including apiaceous vegetables, such as carrots, parsnips, celery, and parsley may reduce the carcinogenic effects of aflatoxin.[26]

Aflatoxin B1 can cause immune suppression, and exposure to it is associated with an increased viral load in HIV positive individuals.[27][28]

There is no specific antidote for aflatoxicosis. Symptomatic and supportive care tailored to the severity of the liver disease may include intravenous fluids with dextrose, active vitamin K, B vitamins, and a restricted, but high-quality protein diet with adequate carbohydrate content.

Detection in humans

There are two principal techniques that have been used most often to detect levels of aflatoxin in humans.

The first method is measuring the AFB1-guanine adduct in the urine of subjects. The presence of this breakdown product indicates exposure to aflatoxin B1 during the past 24 hours. This technique measures only recent exposure, however. Due to the half-life of this metabolite, the level of AFB1-guanine measured may vary from day to day, based on diet, it is not ideal for assessing long-term exposure.

Another technique that has been used is a measurement of the AFB1-albumin adduct level in the blood serum. This approach provides a more integrated measure of exposure over several weeks or months.

Animals

In dogs, aflatoxin has potential to lead to liver disease. Low levels of aflatoxin exposure require continuous consumption for several weeks to months in order for signs of liver dysfunction to appear.[29] Some articles have suggested the toxic level in dog food is 100–300 ppb and requires continuous exposure or consumption for a few weeks to months to develop aflatoxicosis.[30] No information is available to suggest that recovered dogs will later succumb to an aflatoxin-induced disease.

Turkeys are extremely susceptible to aflatoxicosis. Recent studies have revealed that this is due to the efficient cytochrome P450 mediated metabolism of aflatoxin B1 in the liver of turkeys and deficient glutathione-S-transferase mediated detoxification.[31][32]

Some studies on pregnant hamsters showed a significant relationship between exposure of aflatoxin B1 (4 mg/kg, single dose) and the appearance of developmental anomalies in their offspring.[33]

In 2005, Diamond Pet Foods discovered aflatoxin in a product manufactured at their facility in Gaston, South Carolina.[34][35] In 23 states, Diamond voluntarily recalled 19 products formulated with corn and manufactured in the Gaston facility. Testing of more than 2,700 finished product samples conducted by laboratories confirmed that only two date codes of two adult dog formulas with the "Best By" dates of April 3, April 4, April 5, and April 11 had the potential to be toxic.[36]

List of outbreaks

International sources of commercial peanut butter, cooking oils (e.g. olive, peanut and sesame oil), and cosmetics have been identified as contaminated with aflatoxin.[37][38][39] In some instances, liquid chromatography-tandem mass spectrometry (LC-MS/MS), and other analytical methods, revealed a range from 48% to 80% of selected product samples as containing detectable quantities of aflatoxin. In many of these contaminated food products, the aflatoxin exceeded the safe limits of the U.S. Food and Drug Administration (FDA), or other regulatory agency.[38][39][40]

  • 2003 Kenya: acute poisoning, 120 confirmed deaths.[41][42]
  • February–March 2013: Romania, Serbia, Croatia imported into western Europe - 2013 aflatoxin contamination.
  • February 2013: Iowa contamination.[43]
  • 2014 (ongoing): Nepal and Bangladesh, neonatal exposures, found in umbilical cord blood.[41]

See also

Notes

  1. ↑ 1.0 1.1 Fratamico, Pina M.; Bhunia, Arun K.; Smith, James L. (2008). Foodborne Pathogens: Microbiology and Molecular Biology. Norofolk, UK: Horizon Scientific Press. ISBN 978-1-898486-52-7. 
  2. ↑ Iqbal, Shahzad Zafar (2014). "Natural incidence of aflatoxins, ochratoxin A and zearalenone in chicken meat and eggs". Food Control 43: 98–103. doi:10.1016/j.foodcont.2014.02.046. 
  3. ↑ "Aflatoxins and growth impairment: a review". Critical Reviews in Toxicology 41 (9): 740–55. October 2011. doi:10.3109/10408444.2011.575766. PMID 21711088. 
  4. ↑ 4.0 4.1 Abbas, Hamed K. (2005). Aflatoxin and Food Safety. CRC Press. ISBN 0-8247-2303-1. 
  5. ↑ "The Potential Role of Mycotoxins as a Contributor to Stunting in the SHINE Trial". Clinical Infectious Diseases 61 Suppl 7: S733-7. December 2015. doi:10.1093/cid/civ849. PMID 26602301. 
  6. ↑ "Association of aflatoxin exposure and height-for-age among young children in Guatemala". International Journal of Environmental Health Research: 1–13. April 2018. doi:10.1080/09603123.2018.1468424. PMID 29706087. 
  7. ↑ "Aflatoxin exposure in utero causes growth faltering in Gambian infants". International Journal of Epidemiology 36 (5): 1119–25. October 2007. doi:10.1093/ije/dym122. PMID 17576701. 
  8. ↑ "Aflatoxin exposure during the first 36 months of life was not associated with impaired growth in Nepalese children: An extension of the MAL-ED study". PLOS One 12 (2): e0172124. 2017. doi:10.1371/journal.pone.0172124. PMID 28212415. 
  9. ↑ "Exposure to aflatoxin and fumonisin in children at risk for growth impairment in rural Tanzania". Environment International 115: 29–37. March 2018. doi:10.1016/j.envint.2018.03.001. PMID 29544138. 
  10. ↑ "The Potential Role of Mycotoxins as a Contributor to Stunting in the SHINE Trial". Clinical Infectious Diseases 61 Suppl 7 (Suppl 7): S733-7. December 2015. doi:10.1093/cid/civ849. PMID 26602301. 
  11. ↑ "Mitigating aflatoxin exposure to improve child growth in Eastern Kenya: study protocol for a randomized controlled trial". Trials 16: 552. December 2015. doi:10.1186/s13063-015-1064-8. PMID 26634701. 
  12. ↑ Hudler, George W. (1998). Magical Mushrooms, Mischievous Molds: The Remarkable Story of the Fungus Kingdom and Its Impact on Human Affairs. Princeton University Press. ISBN 978-0-691-07016-2. https://books.google.com/books?id=Bob1Uo_hNTgC. 
  13. ↑ "Human skin penetration of selected model mycotoxins". Toxicology 301 (1-3): 21–32. November 2012. doi:10.1016/j.tox.2012.06.012. PMID 22749975. 
  14. ↑ Guidance for Industry: Action Levels for Poisonous or Deleterious Substances in Human Food and Animal Feed. Food and Drug Administration. August 2000. http://www.fda.gov/Food/GuidanceComplianceRegulatoryInformation/GuidanceDocuments/ChemicalContaminantsandPesticides/ucm077969.htm#afla. Retrieved March 10, 2013. 
  15. ↑ Wannop, C. C. (March 1961). "The Histopathology of Turkey "X" Disease in Great Britain". Avian Diseases 5 (4): 371–381. doi:10.2307/1587768. 
  16. ↑ Boutrif, E. (1998). "Prevention of aflatoxin in pistachios". Food, nutrition and agriculture 21. http://www.fao.org/docrep/W9474T/w9474t06.htm. 
  17. ↑ "The phylogenetics of mycotoxin and sclerotium production in Aspergillus flavus and Aspergillus oryzae". Fungal Genetics and Biology 31 (3): 169–79. December 2000. doi:10.1006/fgbi.2000.1215. PMID 11273679. https://naldc.nal.usda.gov/naldc/download.xhtml?id=35468&content=PDF. 
  18. ↑ Aflatoxin M2 product page from Fermentek
  19. ↑ Smith, John E.; Sivewright-Henderson, Rachel (1991). Mycotoxins and animal foods. CRC Press. p. 614. ISBN 978-0-8493-4904-1. https://books.google.com/books?id=pNZHeXG8DJQC&pg=PA614. 
  20. ↑ No chance for aflatoxins Rural 21, the International Journal for Rural Development, 3 April 2013. -- The Aflacontrol project was conducted by IFPRI with scientists from CIMMYT, the International Crops Research Institute for the Semi-Arid Tropics (ICRISAT), Directorate of Groundnut Research and other organizations. It sought to provide evidence of the cost-effectiveness of aflatoxin risk-reduction strategies along maize and groundnut value chains in Africa, and to understand what prevented adoption of these control strategies.
  21. ↑ "Determination of aflatoxin B1 levels in organic spices and herbs". TheScientificWorldJournal 2013: 874093. 2013. doi:10.1155/2013/874093. PMID 23766719. 
  22. ↑ "Human aflatoxicosis in developing countries: a review of toxicology, exposure, potential health consequences, and interventions". The American Journal of Clinical Nutrition 80 (5): 1106–22. November 2004. doi:10.1093/ajcn/80.5.1106. PMID 15531656. http://www.ajcn.org/content/80/5/1106.full. 
  23. ↑ "Association of aflatoxin with gallbladder cancer in Chile". JAMA 313 (20): 2075–7. May 2015. doi:10.1001/jama.2015.4559. PMID 26010638. 
  24. ↑ "Aflatoxin B1 induces the transversion of G-->T in codon 249 of the p53 tumor suppressor gene in human hepatocytes". Proceedings of the National Academy of Sciences of the United States of America 90 (18): 8586–90. September 1993. doi:10.1073/pnas.90.18.8586. PMID 8397412. 
  25. ↑ Aspergillus: Molecular Biology and Genomics. Caister Academic Press. 2010. ISBN 978-1-904455-53-0. 
  26. ↑ "Apiaceous vegetable constituents inhibit human cytochrome P-450 1A2 (hCYP1A2) activity and hCYP1A2-mediated mutagenicity of aflatoxin B1". Food and Chemical Toxicology 44 (9): 1474–84. September 2006. doi:10.1016/j.fct.2006.04.010. PMID 16762476. http://linkinghub.elsevier.com/retrieve/pii/S0278-6915(06)00098-6. 
  27. ↑ "Association between high aflatoxin B1 levels and high viral load in HIV-positive people". World Mycotoxin Journal 6 (3): 255–261. 2013. doi:10.3920/WMJ2013.1585. 
  28. ↑ "Common food fungus can accelerate onset of AIDS". digitaljournal.com. September 1, 2013. http://www.digitaljournal.com/article/357485. 
  29. ↑ "Potential for dietary protection against the effects of aflatoxins in animals". Journal of the American Veterinary Medical Association 222 (5): 591–6. March 2003. doi:10.2460/javma.2003.222.591. PMID 12619837. 
  30. ↑ "Pathological findings in a natural outbreak of aflatoxicosis in dogs". The Onderstepoort Journal of Veterinary Research 54 (4): 635–40. December 1987. PMID 3444619. 
  31. ↑ "Cloning, expression and functional characterization of cytochrome P450 3A37 from turkey liver with high aflatoxin B1 epoxidation activity". Chemical Research in Toxicology 23 (8): 1322–9. August 2010. doi:10.1021/tx1000267. PMID 20707407. 
  32. ↑ "Metabolism of aflatoxin B1 in turkey liver microsomes: the relative roles of cytochromes P450 1A5 and 3A37". Toxicology and Applied Pharmacology 254 (3): 349–54. August 2011. doi:10.1016/j.taap.2011.05.010. PMID 21616088. 
  33. ↑ Goldblatt, Leo (2012-12-02). Aflatoxin: Scientific Background, Control, and Implications. ISBN 9780323148498. https://books.google.com/?id=0rhSiCG3Ii4C&pg=PA136&lpg=PA136&dq=aflatoxin+pregnancy#v=onepage&q=aflatoxin%20pregnancy&f=false. 
  34. ↑ FDA Inspection Report-Diamond Gaston SC Plant 12/21/2005-1/19/2006.
  35. ↑ 2005 Recall, FDA
  36. ↑ AKC Standard Article Contaminated Diamond Pet Food Products and 'Best By' Dates Narrowed Akcstandard.com
  37. ↑ "Determination of aflatoxins B1, B2, G1, and G2 in olive oil, peanut oil, and sesame oil". Journal of AOAC International 93 (3): 936–42. 2010. PMID 20629398. 
  38. ↑ 38.0 38.1 "Natural occurrence of aflatoxins in Chinese peanut butter and sesame paste". Journal of Agricultural and Food Chemistry 57 (9): 3519–24. May 2009. doi:10.1021/jf804055n. PMID 19338351. 
  39. ↑ 39.0 39.1 "Rapid analytical method for the determination of aflatoxins in plant-derived dietary supplement and cosmetic oils". Journal of Agricultural and Food Chemistry 58 (7): 4065–70. April 2010. doi:10.1021/jf9039028. PMID 20235534. 
  40. ↑ "Determination of aflatoxins in commercial nuts and nut products using liquid chromatography tandem mass spectrometry". World Mycotoxin Journal 4 (2): 119–127. 1 January 2011. doi:10.3920/WMJ2010.1229. 
  41. ↑ 41.0 41.1 "Aflatoxin threat in Nepal, Bangladesh". SciDev.Net South Asia. 2014-12-17. http://www.scidev.net/south-asia/health/news/aflatoxin-threat-in-nepal-bangladesh.html. 
  42. ↑ "Eastern and Southern Africa 2011 Highlights". ICRISAT. 2012. http://exploreit.icrisat.org/sites/default/files/uploads/1379055131_ESA-Res-2011.pdf. 
  43. ↑ "Dog food recall underscores toxic danger in drought-hit U.S. corn". Reuters. February 25, 2013. https://www.reuters.com/article/usa-corn-aflatoxin-idUSL1N0BP9SP20130225. 

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