Aflatoxins are variouspoisonouscarcinogens andmutagens that are produced by certainmolds, particularlyAspergillus species mainly byAspergillus flavus andAspergillus parasiticus. According to theUSDA, "They are probably the best known and most intensively researchedmycotoxins in the world."[1] The fungi grow in soil, decaying vegetation and variousstaple foodstuffs and commodities such as hay,maize (corn),peanuts,coffee,wheat,millet,sorghum,cassava,rice,chili peppers,cottonseed,tree nuts,sesame seeds,sunflower seeds, and various cereal grains and oil seeds. In short, the relevant fungi grow on almost any crop or food. When such contaminated food is processed or consumed, the aflatoxins enter the general food supply. 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 milk, milk products, and meat.[2] For example, contaminated poultry feed is the suspected source of aflatoxin-contaminated chicken meat and eggs in Pakistan.[3]
Children are particularly vulnerable to aflatoxin exposure, which is linked toimmune suppression,stunted growth,[4] delayed development,[5] aflatoxicosis,[6] andliver cancer. Some studies have reported an association between childhood stunting and aflatoxin exposure, although this link has not been consistently detected in all studies.[7][8][9][10] Furthermore, a causal relationship between childhood stunting and aflatoxin exposure has yet to be conclusively shown by epidemiological studies, though such investigations are underway.[11][12][13] Adults have a higher tolerance to exposure, but are also at risk. No animal species is known to be immune. Aflatoxins are among the mostcarcinogenic substances known.[14] After entering the body, aflatoxins may be metabolized by the liver to a reactiveepoxide intermediate or hydroxylated to become the less harmful aflatoxin M1.
Aflatoxin poisoning most commonly results from ingestion, but the most toxic aflatoxin compound, B1, can permeate through the skin.[15]
TheUnited States Food and Drug Administration (FDA) action levels for aflatoxin present in food orfeed is 20 to 300 ppb.[16] 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 the speciesAspergillus flavus, in which some of the compounds first were discovered. A new disease was identified with unknown characteristics in England during the 1950s and 1960s, which increased turkey mortality. Later, aflatoxin was recognized in 1960 in England as a causative agent of the mysteriousTurkey X disease that causes excessive mortality in turkey poults.[17] Aflatoxins form one of the major groupings ofmycotoxins, and apart fromAspergillus flavus various members of the group of compounds occur in species such asAspergillus parasiticus,Aspergillus pseudocaelatus,Aspergillus pseudonomius, andAspergillus nomius.[18]
Aflatoxin B1 is considered the most toxic and is produced by bothAspergillus flavus andAspergillus parasiticus.Aflatoxin M1 is present in the fermentation broth ofAspergillus parasiticus, but it and aflatoxin M2 are also produced when an infected liver metabolizes aflatoxin B1 and B2.
Aflatoxin B1 and B2 (AFB), produced byA. flavus andA. parasiticus
Aflatoxin G1 and G2 (AFG), produced by some Group IIA. flavus andAspergillus parasiticus[19]
Aflatoxin M1 (AFM1), metabolite of aflatoxin B1 in humans and animals (exposure inng levels may come from a mother's milk)
Aflatoxin M2, metabolite of aflatoxin B2 in milk of cattle fed on contaminated foods[20]
Aflatoxicol (AFL): metabolite produced by breaking down the lactone ring
Aflatoxin Q1 (AFQ1), major metabolite of AFB1 inin vitro liver preparations of other higher vertebrates[21]
AFM, AFQ, and AFL retain the possibility to become an epoxide. Nevertheless, they appear much less capable of causingmutagenesis than the unmetabolized ABM.[22]
Aflatoxins are produced by bothAspergillus flavus andAspergillus 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. Aflatoxin contamination is increasing in crops such asmaize as a result ofclimate change creating better conditions for these molds.[23][24]
The native habitat ofAspergillus 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 for production of aflatoxins include highmoisture content (at least 7%) and temperatures from 55 to 104 °F (13 to 40 °C) [optimum 27 to 30 °C (81 to 86 °F)].[25][26] 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.[2][27]
A study conducted inKenya andMali found that the predominant practices for drying and storage of maize were inadequate in minimizing exposure to aflatoxins.[28]
Organic crops, which are not treated withfungicides, may be more susceptible to contamination with aflatoxins.[29]
Shine emitted by aflatoxins under ultraviolet light at right. At left, the same fruit under natural light.
A primary means of limiting risk from aflatoxins in the food supply isfood hygiene in the commercial commodity supply chain, such as rejecting moldy grain for use infood processing plants and testing of batches of ingredients for aflatoxin levels before adding them to the mix. Regulatory agencies such as the FDA set limits on acceptable levels.Grain drying itself, which isnecessary for viable combine harvesting in many regions, lays the fundamentals for this effort by preventing stored grain from being too damp in the first place.
There is very limited evidence to show that agricultural and nutritional education can reduce exposure to aflatoxin in low to middle income countries.[30]
No animal species is known to be immune to theacute toxic effects of aflatoxins. Adult humans have a high tolerance for aflatoxin exposure and rarely succumb to acute aflatoxicosis,[31] but children are particularly affected, and their exposure can lead to stunted growth and delayed development, in addition to all the symptoms mentioned below.[5]
High-level aflatoxin exposure produces an acutehepaticnecrosis (acute aflatoxicosis), resulting later incirrhosis orcarcinoma of the liver. Acute liver failure is made manifest bybleeding,edema, alteration in digestion, changes to the absorption and/or metabolism of nutrients, and mental changes and/orcoma.[31]
Chronic,subclinical exposure does not lead to symptoms so dramatic as acute aflatoxicosis. Chronic exposure increases the risk of developing liver and gallbladder cancer,[32] as aflatoxin metabolites mayintercalate into DNA andalkylate the bases through its epoxidemoiety. This is thought to cause mutations in thep53 gene, an important gene in preventing cell cycle progression when there are DNA mutations, or signalingapoptosis (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.[33] As with other DNA-alkylating agents, Aflatoxin B1 can cause immune suppression, and exposure to it is associated with an increasedviral load inHIV positive individuals.[34][35]
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.[36]
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.
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.[38] 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.[39] 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 efficientcytochrome P450 mediated metabolism of aflatoxin B1 in the liver of turkeys and deficientglutathione-S-transferase mediated detoxification.[40][41]
Some studies on pregnant hamsters showed a significant relationship between exposure of aflatoxin B1 (4 mg/kg, single dose) and the appearance ofdevelopmental anomalies in their offspring.[42]
In 2005, Diamond Pet Foods discovered aflatoxin in a product manufactured at their facility inGaston, South Carolina.[43][44] 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 had the potential to be toxic.[45]
In December 2020 and January 2021, Midwestern Pet Foods recalled dog food that contained fatal levels of aflatoxin.[46] As many as 70 dogs had died from aflatoxin poisoning by January 12, 2021.[47]
Schematic summarizing the major AFB1 and AFM1 contamination/exposure routes and adverse health effects to human
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-guanineadduct 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 thehalf-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.
1960 Outbreak of Turkey 'X' disease in England and alatoxin discovery
1961 IdentifiedAspergillus flavus associated with toxicity of groundnuts
1962 Studies conducted on physicochemical properties of aflatoxins, aflatoxin B and G identified in TLC analysis, and isolation and synthesis of crystalline aflatoxins.
1963 Aflatoxin B2, G1, and G2 were identified and chemically characterized as difurocoumarin derivatives
1965 FDA approved the first regulation on aflatoxins 30 μg/kg
1966 Milk toxins were designated as AFM1 and AFM2 and AFM1 was detected in milk, urine, kidney, and liver
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^abLi FQ, Li YW, Wang YR, Luo XY (May 2009). "Natural occurrence of aflatoxins in Chinese peanut butter and sesame paste".Journal of Agricultural and Food Chemistry.57 (9):3519–24.doi:10.1021/jf804055n.PMID19338351.
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