New Zealand Case
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Others have also reported aflatoxin residues in autopsy specimens of children dying of Reye's syndrome. Becroft suggested that contamination of foods by aflatoxin may have a role in the etiology of Reye's syndrome, in an analysis of liver specimens from two children who died of Reye's syndrome (Becroft and Webster, 1972). The amount of aflatoxin B. present was estimated to be in the range of 5 to 50 µg/kg liver in each specimen (5-50 ppb).
Dvorachova et al (1972), reported finding aflatoxin B. in liver specimens of two infants, who died with liver damage and encephalopathy, and later added four more cases of infants, who died similarly and also had detectable concentrations of afitoxin B1 in their livers.
The United States Case
Two reports in the U.S. have suggested an association between Reye's syndrome and aflatoxin exposure. Chaves-Carballo et al., (1976) found fluorescing material chromatographically similar to aflatoxin G2 in the formaldehyde fixed - liver of a 15 year old Reye's syndrome patient. Similar material could not be found in seven other cases or in 12 control.
Rosenberg (1972) decribed the case of a 45-yearold man, who died a short time after an apparent gastric illness. He had eaten an unusually large amount of nuts, which were apparently quite mouldy. The illness was diagnosed as acute yellow atrophy of the liver, but analysis of the liver revealed the presence of a blue fluorescing material which cochromatographed with aflatoxin B. on a thin layer chromatographic (TLC) plate. The author suggests the case may be one of acute aflatoxin poisoning.
Aflatoxin and Sub-acute Poisoning
There are reports which suggest that some outbreaks of sub-acute poisonings concentain resulted from ingestion of large amounts of aflatoxins over a period of time; most of those outbreaks involve children.
1. Possible association with Indian Hepatitis
In October 1974, unseasonal rains in 150 villages in Gujerat and Rajasthan western India resulted in extensive mould damage to standing corn crops. The people in these rural areas were poor and were forced to eat the contaminated grain for lack of altenate foodstuffs. After a few weeks of consuming the mouldy corn, many people became ill with symptoms of liver injury (Krishnamachari, et al, 1975). One hundred and six of 397 patients died. The disease mainly affected male adults and spared infants and children (ages of 6 and 30 years). Patients puffered a sub-acute poisoning with anorexia, vomiting, jaundice and ascites.
Dogs that shared food of affected households also developed ascites and jaundice and died a few weeks after onset. Other domestic animals which did not share the family food were not affected.
Five specimens of mouldy corn were collected from affected households and chemical analysis revealed aflatoxin contents ranging from 6.25 to 15.6 mg/kg corn which is extremely heavy contamination. Aflatoxin B1 was detected in 2 of 7 serum samples collected from patients. Histopathologically, liver specimens revealed extensive bile duct proliferation, periportal fibrosis, and occasional multinucleated giant cells. The authors estimated that the patients had ingested 2 to 6 mg of aflatoxin each day for several weeks.
2. Possible association with Indian Childhood Cirrhosis
In India, liver cirrhosis is the third most common cause of death in hospital among children under the age of 5 years. With its characterically insidious onset, involving low grade fever, mild abdominal distension followed by enlarged liver with a characteristic leafy border, the disease may progress to jaundice, ascites, fibrosis, cirrhosis, and hepatic coma (Yadgiri et al, 1970, Amla et al, 1971). In one episode (Amla, et al, 1967), children suffering from kwashiorkor were given peanut flour supplement for several weeks until it was discovered that the peanut flour contained 300 ppb aflatoxins. Liver biopsies taken 1-2 months after consumption of the toxic meal showed fatty liver while after some 4 months fibrosis and cirrhosis were apparent.
Aflatoxin and Liver Cancer
Geographic distribution of liver cancer
Primary liver cancer is not a common disease in most areas of the world. There are particular geographic areas, however, where the annual liver cancer rate is reported to be well above the level (2 cases per 100,000 people). Certain populations in Africa, southern India, Japan, and Southeast Asia have unusually high incidences of liver cancer.
The hazards from chronic exposures to mycotoxins are potential rather than documented.' The evidence for the association of aflatoxins in the cause of liver cancer has been considered strong enough to justify intervention in the food contamination cycle. However, other factors such as the part played by hepatitis, must be assessed.
Several field studies which have associated consumption of aflatoxins with human liver cancer have been documented. The studies took place from 1966 to 1973 in Uganda, the Philippines, Thailand, Kenya, and Swaziland, in approximately that order.
The pioneering effort in the field associations was undertaken by Alpert et a/, (1971) at Harvard Medical School Massachusetts Institute of Technology,
Food samples were collected during the ninemonth period from September 1966 to June 1967 from village markets and home granaries throughout Uganda by staffs and medical students on vacation leave from Kampala. All food specimens were sealed upon collection and kept in cold storage until shipped by air freight to Boston, for chemical assay for aflatoxins.
Analysis of a total of 480 samples of food (Table 3), revealed 29% containing more than 1 ppb aflatoxin and 4% containing more than 1 ppm. Aflatoxins occurred most frequently in bean (72%), whereas maize (45%) peanut (18%) and cassava (12%) were contaminated less frequently. The aflatoxin concentration sometimes exceeded 1000 ppb.
Table 3: Aflatoxin concentration in some Uganda foodstuffs
|Foodstuff||Not contaminated||Total aflatoxin cone. (ppb)|
|Not assayed (%)||1-100||100-1000||1000|
|Total (%)||142/480 (29)||87 (29)||37 (8)||18 (4)|
At the time the aflatoxin survey was being made, local cancer registry records covering 1964 to 1966 were being studies to estimate the geographical distribution of liver cancer in Uganda.
Table 4 gives the relation between the incidence of liver cancer and the aflatoxin contamination in foodstuffs in Uganda. Hepatoma occurred at an annual rate of 1.0 to 2.7 cases per 100,000 people.
Table 4: Hepatoma incidence and frequency of aflatoxin contamination of foodstuffs in Uganda.
|Area||Hepatoma incidence||% Conta-mination||Aflatoxin contamination of foodstuffs (%)|
|Total aflatoxin cone. (ppb)|
For the Karamojan tribe, hepatoma incidence was 6.8 cases per 100,000 per year, and the frequency of aflatoxin contamination was 44 %.
Over a 23 - month period from September 1967 through July 1969 (Shank et al, 1972) mycological studies on cereal, ok seeds, beans, cassava, dried fish, dried and fresh vegetables and prepared foods showed Aspergillus flavus to be the most common contamination fungus. Penicillium, Fusarium, and Rhizopus fungi were also prevalent.
The consumption of aflatoxin was determined by three separate surveys, each of 2 - day duration, over a period of 1 year. Within the three survey areas of Thailand (Singburi, Ratchaburi and Songkhla), samples of food served were collected, and the amounts of each food eaten by the family were measured. Daily aflatoxin ingestion, expressed as hanograms of total aflatoxins consumed per kilogram body weight on family rather than individual basis (Table 5), was highest in Singburi (73 to 81), intermediate in Ratchaburi (45 to 77), and lowest in Songkhia. (5 to 8).
Table 5: Liver cancer incidence and aflatoxin consumption in Thailand
|Province||Liver cancer incidence (cases/100,000/year)||Average daily aflatoxin intake (ng/kg bo.wt.)|
|Singburi||||51 - 55||73 - 81|
Incidence of liver cancer, as measured in this survey, was two new cases per year in Songkhla and 6 new cases /100,0001 year in Ratchaburi. National health records indicated that the incidence of primary liver cancer in Singburi area was 14 deaths /100,00/ year, but this rate could not be measured directly as part of the aflatoxin study due to the unavailability of a key figure in the study.
Another investigation was conducted in Kenya at the time of the Thailand study (Peers and Linseli, 1973). The main evening meal was sampled over 24 times in sample clusters of individuals distributed in 132 sublocations in the district. The collection period was 21 months. Estimation of the incidence of primary liver cancer in the disrict was based on data from the Kenya Cancer Registry (Table 6).
Table 6: Hepatoma Incidence and aflatoxin consumption in Kenya.
|Altitute area||Liver caner incidence cases/100,000/year (1967-1970)||Average daily aflatoxin B1 intake (ng/kh bo.wt.)|
In the high altitude area, 39 of 808 samples (5%) contained aflatoxins, mean concentration of which was 0.121 ppb. In the middle area, 7% (54/909) of the samples were contaminated with mean concentration of 0.205 ppb; the low altitude area had a highest frequency, 78 of 816 (10%) of the samples, with 0.351 µg/kg, of aflatoxin contamination.
The 1974 Van Rensburg et al study reported results in measuring aflatoxin consumption in Mozambique, in particular the Inhambans district, which showed a liver cancer rate of 35.5 and 25.4/ 105/year for the periods 1964-68 and 1969-71, respectively, with more than twice as many cases in males as in females.
Aflatoxin contamination of prepared foods consumed by the study population was measured by chemical assay of 880 meals. The mean daily per capita consumption of aflatoxins was calculated to be 222.4 mg/kg body weight. Thus, the highest primary liver cancer rate correlates with the highest known aflatoxin intake in the world.
Two studies on aflatoxin and human liver cancer have been performed in Swaziland. In 1971, Keen and Martin found a geographical distribution for aflatoxins in peanut samples from low, middle, and high velds with the distribution of liver cancer cases.
A retrospective survey of primary liver cancer among a group of workers showed that Shangaans had a higher incidence than Swazis, although both tribes were provided with the same lot of groundnut. Interviews from tribal groups indicated that Shangaans ate more peanuts in powder form more often and for longer periods than did the Swazis. The Shangaans powdered the nuts in wooden, fungus - infected mortar, and supplemented their rations with locally purchased groundnut, whereas Swazis did neither of these things.
In 1972, the International Agency for Research on Cancer (IARC) and Tropical Products Institute (TPI) of London initiated a study in Swaziland which was modeled on their earlier study in Murang's district of Kenya.
Table 7: Relation between aflatoxin consumption and liver cancer in Swaziland.
|Area||Average daily AFB1 mtake (ng/kg bo.wt.)||Liver cancer incidence adults/100,000/year|
Aflatoxin determinations were made from 1056 samples of the main meal and 45.5 sample of beer, etc. The result showed clear correlation between estimated aflatoxin consumption and liver cancer rates.
Peanut butter and maize have been shown to be contributors of aflatoxins to the Philippines food products (Campbell and Salamat, 1971). Aflatoxins were found in almost all of the 149 samples of peanut butter, with an average concentration of AFB1 of 213 ppb. The most heavily contaminated sample of peanut butter contained 8.6 ppm AFB1 whereas 95 of 98 maize samples analysed contained an average of 110 ppb AFB1.
Epidemiological studies have associated ingestion of aflatoxins with human liver disease and others in certain populations, but this does not necessarily indicate that the aflatoxins are the sole causative agents.
1. Relation between chemicals and aflatoxins
Diets that can contain appreciable quantities of aflatoxins would appear capable of containing other mycotoxins, i.e. sterigmatocystin, ochratoxin, penicillic acid, etc; organochorine insecticides ie. DDT, Lindane; nitrosamines and certain plant toxins, ie. pyrrolizidine alkaloids, etc.
The synergistic effect of dimethyinitrosmine on liver tumor induced by sterigmatocystin, a fungal product of Aspergillus versicolor which is about ten times less carcinogenic than AFB1 was reported (Terao, et al. 1978). Moreover in our previous study, we also observed the synergistic effect of dimethylintrosamine on liver tumor induced by the most potent hepatocarcinogenic mycotoxin, aflatoxin B. (Angsubhakorn, et a/, 1981).
Table 8: Summay of histopathlogical changes during DMN and AFB1 induced liver cancer in rats at 12 month.
|Diet||Rats with Lesions|
|No. of rats||Foci of cell alteration||Neoplastic nodules||Hepatocellular carcinomas(%)|
|AFB1 + DMN||14||12||11||11(79)|
The alpha isomer of 1, 2, 3, 4, 5, 6 hexachlorooyclohexane of lindane, inhibits the development of liver tumors induced by AFB1 (Table 9) (Angsub hakorn et al, 1978,1981).
Table 9: Liver tumor in long term experiment.
|Experimental group.||Strain of rats|
|??- BHC + AFB1||0/8||0/8|
Our previous work using gamma isomer of lindane supports the previous results demonstrating protection against AFB1 - induced carcinoma in rodent liver after long term administration of high doses of delta - HCH (Angsubhakorn, et al, 1989) (Table 10).
Table 10: Liver tumor in long term experiment.
|Experimental group||No. animals examined||No. liver-tumor-bearing animals (%)|
|2. LD + AF, 1 wk||20||1(5)|
|3. LD + AF, 3 wk||23||0|
|4. LD + AF, 5 wk||17||0|
|5. LD + AF, 10 wk||22||0|
|6. LD + AF, 15 wk||13||0|
|7. LD, 15 wk||18||0|
|8. AF, 15 wk||19||6(315)|
It has indicated that aflatoxin and alcohol when consumed concurrently, can act synergistically in the development of primary liver cancer in man (BulatoJayme et al. 1982) and hepatotoxicity in rats (Toskulkao et. al. 1982).
2. Relation between virus and aflatoxins
Epidemiological evidence strongly implicates both hepatitis B virus and aflatoxin as important agents in the production of hepatocellular carcinoma. Many have speculated that the two factors are co-carcinogens. However, data derived by many workers suggest that the risk of hepatoma -is no greater in chronic H. BV carriers from Mozambique than in those from the U.S.A. The difference between hepatoma-rates in the two countries, therefore, relates significantly to the H.B.V. carrier rate in the population. Aflatoxin may act primarily as an immuno-suppressive agent causing an increase in H.B.V. carriers.
Experimentally, the newly described woodchuck hepatitis virus (Summers, et at, 1978) which morphologically and clinico-pathologically seems strikingly similar to H.RV., could provide an ideal system to test this hypothesis. If this hypothesis proves to be correct, a vaccine to prevent hepatitis B could be used to eradicate hepatoma without the major economic problem of changing farming and crop storage and food consumption by populations likely to be exposed to aflatoxin.
3. Relation between parasites and aflatoxins
Parasitic infectation may influence carcinogens. The northeastern pert of Thailand which has a higher death rate due to liver cancer in adult who suffered to some extent from liver fluke disease, is also an area of high exposure to aflatoxins.
The interaction between human liver flukes nitrosamine and bile-duct tumor was first demonstrated in hamsters (Thamavit et al, 1978). Moreover, interaction between rodent malarial parasite, aflatoxin and hepatic call tumor were also reported (Angsubhakorn, et al, 1986, 1988). The mechanism by which malarial infection enhances or reduces aflatoxin-induced liver tumor has not been determined but may be related to effects of immunologic or metabolic activation of malarial parasite antigen.
4. Relation between other cancer and aflatoxin
Human health risk associated with occupational exposure to aflatoxin-contaminated food stuffs, an issue that has received little attention, should be considered in the present time. Aflatoxincontaminated dust may be a causative factor in the cause of nasal cancer but not cancer of liver.
In Czechoslovakia, two chemical engineers who had worked on a method for sterilizing peanut meal infected with A. flavus were reported to have died from lung cancer. One of them, who died at 68 year of age, had done this work only 3 months, and developed symptoms 3 months later. No details were provided for the second engineer (Dvorachava, 1976).
Two British biochemists developed cancer of the colon after exposure to purified aflatoxins. One of them had worked with this material from 1962 to 1964 and developed symptoms in 1971 at 42 year of age. The second had done this work for 12 months between 1969 and 1970 and developed symptoms in 1972, at 28 years of age (Deger, 1979).
5. Other Possible Cases
It has generally been assumed that exposures to large amounts of aflatoxin and presumably most other mycotoxins occur only in areas of the world with a tropical climate and with agricultural practices not common to the technologically modern countries in the western hemisphere. With greater experience and at closer scrutiny, however, it appears this assumption may not be valid. However, most foodstuff produced and sold in the advanced temperate countries appear to contain at most only trace amounts of aflatoxins.
It is conceivable that silo operators when handling mouldy grains could be exposed to high concentrations of airborne mycotoxins; similar conditions may also occur in a food - processing factory where vegetable oils are obtained from nut and seeds mainly peanut and linseed (Van Nienwenhnize, et at, 1973). During all phases of the process great quantities of dust are created in the work areas, especially during the dumping, transportation and bagging of the residues. The authors estimated a range of exposures for a workweek (45 hr) of 0.039-2.5 µg aflatoxin which is approximately 10 % of the exposure seen in the dietary studies of Asia and Africa. From an epidemiological study, 11 out of 55 workers developed various forms of cancer (4 cases of bronchial carcinomas and carcinoma of the bladder (1), gastrointestinal tract (1), liver (1), maxillary sinus (1), prostate (1), anaplastic carcinoma (1) and pleura mesothelioma).
6. Mycotoxin Residues in Animal Tissues
The greatest demonstrated potentials for encountering mycotoxin residue in edible animal tissue are aflatoxin M in cow's milk and ochratoxin A in swine kidney. Aflatoxin B. is the mycotoxin that has been most extensively studied for possible residues in tissues. The various controlled studies of aflatoxin transmission from feed to edible tissue have been reduced to a table of feed to tissue ratios for cow's milk, chicken eggs, and the livers of cattle, swine and chickens. (Table 11)
Table 11 Ratios of AFB1 levels in feed to AFB1 or M1 levels in edible tissue.
|Animal||Tissue||Aflatoxin in tissue||Feed to tissue ratio|
Most of the eggs and milk data are based on a continuous feeding regimen; the liver data are based on slaughter 18-24 hours after the last exposure of aflatoxin. It is shown that milk is the tissue most vulnerable to aflatoxin contamination, particulary swine feed consumption and lactation are concurrent events, i.e. there is no withdrawal period.
Occurrence of ochratoxin A residues in poultry and swine kidneys was established in Denmark, Sweden and Yugoslavia. The obvious explanation was that both diseases had common cause in ochratoxincontaminated grains used for feed
In the United States, an action level of 0.5 µg/ml has been set for AFM1 in milk and 20 ppb in food. In Denmark, If ochratoxin is detected in the kidneys, the whole carcass will be condemned.
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