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PubMed1988

Cancer risk and occupational exposure to aflatoxins in Denmark.

A study of cancer risk among male employees at 241 livestock feed processing companies in Denmark was conducted on the basis of a data linkage system for detailed investigation of occupational cancer providing employment histories back until 1964, established at the Danish Cancer Registry. Crops imported for feed production have often been contaminated with highly variable concentrations of aflatoxins; an estimated average concentration of at least 140 micrograms aflatoxin B1 kg-1 prepared mixed cattle feed prevailed in the past, yielding a daily intake for workers via the respiratory route of approximately 170 ng. Risk was established on the basis of cancer cases among male workers, whose employment in one of the companies was the job they had held for the longest time since 1964. Elevated risks for liver cancer and for cancers of the biliary tract were observed, which increased by two- to three-fold significance after a 10-year latency. Exposure to aflatoxins in the imported crops was judged to be the most probable explanation for these findings, although the influence of lifestyle factors, e.g. alcohol consumption on the results cannot be fully disregarded. Increased risks for salivary gland tumours and multiple myeloma were also detected. However, due to multiple comparisons carried out in this study these new associations must await further confirmation. A decreased risk for lung cancer was observed; despite possible negative confounding due to the smoking habits of the employees, the lung does not seem to be a target organ for the carcinogenic effect of inhaled aflatoxins in humans.

Adult↗

PubMed1997

Determination of aflatoxin B1-DNA adduct in rat liver by enzyme immunoassay.

A simple, rapid and highly sensitive indirect competitive enzyme-linked immunosorbent assay (ELISA) to determine aflatoxin B1 (AFB1)-DNA adducts is reported. Polyclonal antibodies specific to the aflatoxin B1-N7-guanine adduct were produced using a novel synthetic antigen, bovine serum albumin (BSA)-guanine-AFB1. The antibodies were characterized by the Ouchterlony double diffusion technique and by antibody capture assay. The working range of the indirect competitive assay developed was between 0.45 and 330 ng of the analyte [calf thymus (CT)-DNA-AFB1]. A 50% inhibition was attained at 15 ng of the analyte (CT-DNA-AFB1). The antibody capture assay indicated that the antibody produced cross-reacted 100, 92 and 110% with BSA-guanine-AFB1, CT-DNA-AFB1 and CT-DNA-formamidopyrimidine-AFB1, respectively. When free AFB1 and guanine were used as competing analytes, the antibodies showed < or = 5% and zero cross-reactivity at the 50% inhibition level. Spiking studies indicated a recovery in the range 96-97 and 74-78% when standard CT-DNA-AFB1 was added to 10 mM phosphate buffer (pH 7.2) and control rat liver tissue, respectively. Rats exposed to a single oral dose of 1 mg kg-1 body mass of pure AFB1 were used to validate the method. The AFB1-DNA adduct formed in the liver tissue after 48 h of exposure was determined using the ELISA method developed. The liver AFB1-DNA adduct ranged between 6.06 and 7.94 micrograms mg-1 DNA. The proposed method may find application in the biological monitoring of aflatoxin B1 in molecular epidemiological studies to assess the dietary exposure of aflatoxins.

Aflatoxin B1↗

PubMed1967

The interaction of aflatoxins with purines and purine nucleosides.

From measurements of thermal hyperchromicity and the behaviour of an aflatoxin-DNA mixture on a Sephadex column it was concluded that aflatoxin B(1) is capable of weak binding to single-stranded DNA. The interactions of the aflatoxins (B(1), G(1) and G(2)) with nucleosides result in difference spectra and suggest that the purine bases and the amino group play a role in the binding of all the aflatoxins to DNA.

Adenine↗

PubMed1968

Effects of the hepatotoxic agents retrorsine and aflatoxin B1 on hepatic protein synthesis in the rat.

1. Aflatoxin and the pyrrolizidine alkaloid retrorsine inhibited the incorporation of labelled amino acids into rat liver and plasma proteins in vivo. Inhibition was greater and detected earlier with retrorsine (1hr.) than with aflatoxin (3hr.). 2. Both toxins affected the liver ribosomal aggregates, causing increases in the proportion of monomers plus dimers. The effect of retrorsine was greater than that of aflatoxin. 3. Incorporation of labelled amino acids into proteins of cell-free preparations of liver from rats treated with aflatoxin was lower than in control preparations. The main site of inhibition appeared to be the ribosomes. 4. Both toxins inhibited the incorporation of orotate into liver nuclear RNA 1hr. after administration.

Aflatoxins↗

PubMed1969

A comparative study of the effect of aflatoxin B and actinomycin D on HeLa cells.

1. The cytotoxic effects of aflatoxin B(1) on HeLa cells were examined and effects of short exposures of the cells to the toxin were found to be reversible. 2. Aflatoxin B(1) inhibited the synthesis of both ribosomal and heterodisperse RNA. It is proposed that the toxin's mechanism of action on ribosomal RNA synthesis is related to its inhibitory effect on the maturation of the 45s-ribosomal-RNA precursor. 3. Protein synthesis is inhibited to a greater extent by aflatoxin B(1) than by actinomycin D. In contrast with actinomycin D, aflatoxin B(1) was shown to disaggregate polyribosomes directly.

Aflatoxins↗

PubMed1969

The interaction of aflatoxin B1 with polynucleotides and its effect on ribonucleic acid polymerase.

1. The interaction of aflatoxin B(1) with different polynucleotides was studied spectrophotometrically. Equations were derived that enable the degree of binding to be determined without first determining the extinction coefficient of the bound form. 2. The interaction with calf thymus DNA obeys first-order relationships with an association constant of 0.40mm(-1), but there is some evidence for a secondary binding process from results obtained at 390nm. 3. The spectral shifts decreased in the order polyadenylic acid+polyuridylic acid>DNA>polyadenylic acid>polyadenylic acid+polyinosinic acid. Polycytidylic acid, polyuridylic acid, polyinosinic acid (both single- and triple-stranded), AMP, CMP, GMP and UMP did not interact with aflatoxin. It was concluded that there is a requirement for the amino group of adenine (or possibly guanine) for binding of aflatoxin to polynucleotides to occur. 4. Binding is reversed by increasing ionic strength, and by Mn(2+) and Mg(2+) in the concentration range studied (0-5mm). The effect of the Mn(2+) or Mg(2+) was far greater than would be expected on the basis of their ionic strength. With both the bivalent cations and sodium chloride the reversal is greatest with double-stranded polynucleotides. 5. Inhibition in vitro of the DNA-dependent RNA polymerase of Escherichia coli by aflatoxin B(1) was detected only in the absence of Mg(2+) and at concentrations of Mn(2+) below the optimum for RNA synthesis in vitro. 6. The degree of inhibition (maximally 30%) was dependent on the concentration of Mn(2+) and decreased during incubation.

Adenine Nucleotides↗

PubMed1998

Aflatoxin B1 and sulphobromophthalein binding to the dimeric human glutathione S-transferase A1-1: a fluorescence spectroscopic analysis.

The binding interactions between dimeric human class alpha glutathione S-transferase A1-1 (GST A1-1) and aflatoxin B1 or sulphobromophthalein (BSP) were characterised. Aflatoxin B1 binds to GST A1-1 with a stoichiometry of 1.1 mol/mol of dimeric enzyme. The binding interaction, which can be described by a hyperbolic saturation isotherm (Kd = 8+/-2 microM), does not induce major structural changes in the enzyme, nor does it inhibit enzymatic activity. The average distance between the single tryptophan residue (Trp20) of GST A1-1 and protein-bound aflatoxin B1 was calculated to be 22.7 A by means of fluorescence resonance energy transfer. The aflatoxin-binding region, according to this calculated distance, was determined to be located in the dimer interface cleft near the crystallographic two-fold axis. Hill-plot analyses suggest that a positive co-operative interaction exists between BSP and the dimeric GST A1-1 (h = 1.6+/-0.1; K' = 14+/-0.6 microM). The binding of BSP induces a conformational change in the enzyme which is accompanied by a decrease in the molecular flexibility and in the solvent-accessible properties of the enzyme's Trp20 residue. Site-directed mutagenesis of Trp20 (Trp20-->Phe) confirms that this residue is situated in the binding environment and although it is not essential for BSP binding, it is involved in the interaction. Furthermore, the structural change associated with BSP binding alters the hyperbolic character of the glutathione saturation curve. This indicates that there may also be a cooperative interaction between glutathione and BSP or that BSP binding induces asymmetric functioning of the two enzyme subunits so that they become unequal in catalytic activity.

Aflatoxin B1↗

PubMed1999

Inhibition of growth and aflatoxin biosynthesis of Aspergillus flavus by extracts of some Egyptian plants.

The effect of five different concentrations (2, 4, 6, 8 and 10 mg ml-1) of an aqueous extracts of Lupinus albus, Ammi visnaga and Xanthium pungens were tested on growth and aflatoxin production by Aspergillus flavus in a chemically defined medium. All the plants inhibited mycelial growth and aflatoxin formation. The inhibitory effect was proportional with the applied concentration. Growth and aflatoxin production appeared to be correlated processes. The nature of the plant extract also affected the ratio of B1 to B2, and there was no correlation between the inhibition of aflatoxins or growth of the fungus and the resultant B1: B2 ratio.

Aflatoxins↗

PubMed2001

Differentiation of aflatoxin-producing and non-producing strains of Aspergillus flavus group.

AIMS: Three conventional methods and a multiplex PCR procedure with a set of four primers (Quadruplex-PCR) were used to differentiate between aflatoxin-producing and non-producing strains of the Aspergillus flavus group. METHODS AND RESULTS: By combining sets of primers for aflR, nor-1, ver-1 and omt-A genes of the aflatoxin biosynthetic pathway, Quadruplex-PCR showed that aflatoxinogenic strains gave a quadruplet pattern, indicating the presence of all the genes involved in the aflatoxin biosynthetic pathway which encode for functional products. Non-aflatoxinogenic strains gave varying results with one, two, three or four banding patterns. A banding pattern in three non-aflatoxinogenic strains resulted in non-differentiation between these and aflatoxinogenic strains. CONCLUSION AND SIGNIFICANCE AND IMPACT OF THE STUDY: Because conventional methods are time-consuming, further studies are needed to develop a rapid and objective technique that permits complete differentiation between aflatoxin-producing and non-producing strains of the A. flavus group.

Aflatoxin B1↗

PubMed1996

Binding of the aflatoxin-glutathione conjugate to mouse glutathione S-transferase A3-3 is saturated at only one ligand per dimer.

The binding of two different reaction products (p-nitrobenzyl glutathione and the aflatoxin-glutathione conjugate) to mouse glutathione S-transferase A3-3 (mGSTA3-3) has been measured using equilibrium dialysis and a direct fluorescence quenching technique. As expected, p-nitrobenzyl glutathione was found to bind with a stoichiometry of 2.24 +/- 0.17 mol/mol of dimeric enzyme. However, the much larger aflatoxin-glutathione conjugate, 8, 9-dihydro-8-(S-glutathionyl)-9-hydroxyl-aflatoxin B1 (AFB-GSH), was found to bind with a stoichiometry of 1.12 +/- 0.08 mol/mol of dimeric enzyme. p-Nitrobenzyl glutathione bound mGSTA3-3 with a dissociation constant (Kd) of 59 +/- 17 microM while the aflatoxin-glutathione conjugate bound the enzyme with a Kd of 0.86 +/- 0.19 microM. Glutathione competitively inhibited binding of AFB-GSH to mGSTA3-3 with a Ki of 1.5 mM, suggesting that AFB-GSH was binding to the enzyme active site. Although AFB-GSH bound to mGSTA3-3 with a stoichiometry of 1 mol/mol of dimeric enzyme, AFB-GSH completely inhibited activity toward 1-chloro-2, 4-dinitrobenzene, indicating that AFB-GSH binding to one active site alters affinity for 1-chloro-2,4-dinitrobenzene in the active site of the other subunit. To our knowledge, this is the first report of a glutathione S-transferase reaction product which binds to the enzyme with a stoichiometry of 1 mol/mol of dimer.

Aflatoxin B1↗

PubMed1998

Aflatoxin exposure produces serum alphafetoprotein elevations and marked oval cell proliferation in young male Pekin ducklings.

Feeding of aflatoxin to ducks produces extensive oval cell proliferation in the liver associated with a prolonged elevation of serum alphafetoprotein (AFP). Short term feeding of 0.075-0.6 microgram/g of aflatoxin to young male Pekin ducks results in rapid and massive dose-related proliferation of "oval" cells, which extend from the portal zone across the hepatic lobule within three to five weeks. Longer term feeding of 0.15 microgram/g and 0.3 microgram/g results in prolonged elevations of serum AFP. Prolonged elevation of serum AFP serves as a marker of oval cell proliferation preceding hepatocellular carcinoma (HCC) development. These results confirm that ducks are sensitive to low amounts of aflatoxin and develop early lesions that have been shown in other studies to be associated with hepatocarcinogenesis. These findings in ducks support the likelihood that aflatoxin exposure contributes to the risk for development of HCC in humans.

Administration, Oral↗

PubMed2002

Metabolism and cytotoxicity of aflatoxin b1 in cytochrome p-450-expressing human lung cells.

The mycotoxin aflatoxin B(1) (AFB(1)) is a hepatocarcinogen in many animal models and probably a human carcinogen. Besides being a dietary carcinogen, AFB(1) has been detected in dusts generated in the processing and transportation of AFB(1)-contaminated products. Inhalation of grain dusts contaminated with AFB(1) may be a risk factor in human lung cancer. Aflatoxin B(1) requires cytochrome P-450 (CYP)-mediated activation to form cytotoxic and DNA-reactive intermediates, and this activation in human liver is mediated by the CYP 1A2 and 3A4 isoforms. Which isoforms are important in AFB(1) activation in human lung is not well understood. To investigate whether these CYPs can activate AFB(1) at low, environmentally relevant concentrations in human lung cells, SV40 immortalized human bronchial epithelial cells (BEAS-2B) that were transfected with cDNA for CYPs 3A4 (B3A4) or 1A2 (B-CMV1A2) were used. B-CMV1A2 cultured in 15 nM AFB(1) produced the AFB(1)-glutathione conjugate (AFB(1)-GSH) and aflatoxin M(1) (AFM(1)), while B3A4 cells produced only aflatoxin Q(1) (AFQ(1)) at 0.15 microM AFB(1). Nontransfected BEAS-2B cells produced no metabolites, even at 1.5 mM AFB(1). Microsomes prepared from B-CMV1A2 and B3A4 cells activated AFB(1) to AFB(1) 8,9-epoxide (AFBO), while those from BEAS-2B cells did not produce AFBO. Cytosol from all three cell types was ineffective at glutathione S-transferase (GST)-mediated trapping of enzymatically generated AFB(1) 8,9-epoxide. B-CMV1A2 cells were 100-fold more sensitive to AFB(1) compared to B3A4 cells, and were 6000-fold more sensitive than control BEAS-2B cells. Western immunoblots confirmed that only B-CMV1A2 cells expressed CYP 1A2 protein, while CYP 3A4 was only in B3A4 cells. B-CMV1A2 cells were the most sensitive to AFB(1), followed by B3A4 cells. CYP 3A4, which has been predicted to activate AFB(1) primarily at higher AFB(1) concentrations, was also responsible for significant AFB(1) toxicity at low concentrations. These data indicate that human lung cells expressing these CYP isoforms are capable of activating AFB(1), even at environmentally relevant concentrations.

Aflatoxin B1↗

PubMed2001

Absorption, distribution and excretion of aflatoxin-derived ammoniation products in lactating cows.

Peanut meal naturally contaminated with 3.5 mg/kg aflatoxin B1 (AFB1) was spiked with radiolabelled AFB1 (meal 14C-I0) and decontaminated by a small-scale copy of an industrial ammoniation process (meal 14C-I1). During the process 15% of the radioactivity was lost, whereas 90% of the remaining radiolabel could not be extracted from the meal. In the extractable part, AFB1 accounted for 10% of the radiolabel, consistent with a total AFB1 reduction of more than 99%. No degradation products were observed in the extracts. Four lactating cows were fed with a diet containing 15% of either meal 14C-I0 or 14C-I1 for 10 days. On day 9 of this treatment, respectively 23 and 67% of the radiolabel was excreted in the urine and faeces of cows fed meal 14C-I0, as compared with 2 and 101% in the case of cows fed meal 14C-I1. Milk contained respectively 1.35 (meal 14C-I0) and 0.25% (meal 14C-I1) of the radiolabel. Milk samples taken during the equilibrium stage contained respectively 5 and 0.5 ng/ml of AFB1-derived compounds. Aflatoxin M1 (AFM1) accounted for 50-80% of these compounds in the case of milk from cows fed 14C-I0, as compared with 6-20% in the case of 14C-I1. AFB1 to AFM1 carry-over rates for 14C-I0 or 14C-I1 were estimated to be respectively 0.5 and 5.9%. Only liver and kidney samples contained detectable levels of the radiolabel, being respectively 260 and 37 micrograms/kg for cows fed meal 14C-I0, and 10 and 3 micrograms/kg for those fed meal 14C-I1. In the latter case, more than 55% of the radiolabel in the liver could not be extracted, as compared with 90% in the group fed meal 14C-I1. A small part of the extractable radiolabel in the livers of cows fed meal 14C-I0 could be attributed to AFB1 and AFM1 (less than 1% of total radioactivity). In the case of the animals fed 14C-I1 there were indications for the presence of AFB1 and AFM1 (6% of total radioactivity). Decontamination of the highly contaminated (non-radiolabelled) peanut meal by two different industrial ammoniation processes, resulted in a similar reduction of the initial AFB1 levels of 3.5 mg/kg to 15 micrograms/kg. Feeding of diets containing 15% of the non-treated and two treated peanut meals to cows for a period of 10 days, resulted in AFM1 levels in milk of respectively 2.1, 0.04 and 0.07 ng/ml. AFB1 to AFM1 carry-over rates were calculated to be respectively 0.5, 2.0, and 3.6%. It is concluded that the efficient reduction of aflatoxin levels by ammoniation of contaminated peanut meal results in a strong reduction of aflatoxin-related residues in milk and meat of cows, most likely caused by a decreased bioavailability of the degradation products.

Aflatoxins↗

PubMed2001

Differences detected in vivo between samples of aflatoxin-contaminated peanut meal, following decontamination by two ammonia-based processes.

A sample of peanut meal, highly contaminated with aflatoxins, has been subjected to decontamination by two commercial ammonia-based processes. The original contaminated and the two decontaminated meals were fed to rats for 90 days. No lesions associated with aflatoxin-induced hepatocarcinogenesis were detected histologically following feeding with the two detoxified meals. There were, however, clear differences between the two meals in respect of growth rates of the rats. In addition, feeding one of the detoxified meals resulted in hepatic abnormalities detected using novel immunohistochemical reagents. Differences between the two detoxified meals were also indicated by the results of studies using meals 'spiked' with [14C]-aflatoxin B1 prior to being subjected to the detoxification processes. The meals differed in the bioavailability of the label. It was concluded that peanut meal where an initial, unacceptable level of contamination with aflatoxins had been reduced by two ammonia-based processes to comparable, acceptable levels, may still have different effects in vivo when incorporated into animal diets.

Aflatoxins↗

PubMed2001

Genotoxicity testing of extracts from aflatoxin-contaminated peanut meal, following chemical decontamination.

One of the most important concerns in the decontamination of aflatoxin-containing feed commodities is the safety of the products for food-producing animals and for human consumption of products derived from these animals. A new method, based on the use of florisil and C18 solid phase extraction columns, was developed for the preparation of extracts from decontaminated peanut meal, which allowed testing with in vitro genotoxicity assays without interference of the residual aflatoxin B1. Recovery of degradation products in the extracts was evaluated by the use of radiolabelled [14C]-aflatoxin B1 (AFB1) added to naturally-contaminated peanut meal (3.5 mg AFB1/kg). The meal was treated by a small-scale version of an industrial decontamination process based on ammoniation. Following decontamination, more than 90% of the label could not be extracted from the meal. AFB1 accounted for about 10% of the radiolabel present in the extractable fraction, indicating a total AFB1 reduction of more than 99%. Decontamination of the meal by a number of other small- and industrial-scale ammonia-based processes resulted in similar efficiencies. Application of the extraction procedure resulted in AFB1-rich and AFB1-poor fractions, the latter containing half of the extractable decontamination products but less than 1% of the residual AFB1. Testing in the Salmonella/microsome mutagenicity assay (TA 100, with S9-mix) of the original crude extracts and AFB1-rich fractions prepared from non-treated and decontaminated meal, showed the positive results expected from the AFB1 contents as determined by HPLC analysis. Analysis and testing of the AFB1-poor fractions showed that the various decontamination processes not only resulted in a successful degradation of AFB1 but also did not produce other potent mutagenic compounds. Slight positive results obtained with these extracts were similar for the untreated and treated meals and may be due to unknown compounds originally present in the meal. Results obtained with an unscheduled DNA synthesis (UDS) and Comet assay with rat hepatocytes supported this conclusion. Positive results obtained with the micronucleus assay, using immortalized mouse hepatocytes (GKB), did not clearly reflect the mycotoxin levels and require further examination. It is concluded that the newly developed extraction procedure yields highly reproducible fractions and hence is very suitable for examining the possible formation of less potent degradation products of aflatoxins in short-term genotoxicity tests.

Aflatoxins↗

PubMed2001

Aflatoxins in spices marketed in Portugal.

Seventy-nine prepackaged samples of 12 different types of spice powders (five cardamom, five cayenne pepper, eight chilli, five cloves, seven cumin, five curry) powder, five ginger, five mustard, 10 nutmeg, 12 paprika, five saffron and seven white pepper) were selected from supermarkets and ethnic shops in Lisbon (Portugal) for estimation of aflatoxins by immunoaffinity column clean-up followed by HPLC. Aflatoxin B1 (AFB1) was detected in 34 samples of prepackaged spices (43.0%). All of the cayenne pepper samples were contaminated with levels ranging from 2 to 32 microg AFB1/kg. Three nutmeg samples contained levels ranging from 1 to 5 microg/kg, three samples had levels ranging from 6 to 20 microg/kg, and there were two with 54 microg/kg and 58 microg/ kg. Paprika contained levels of aflatoxin B1 ranging from 1 to 20 microg/kg. Chilli, cumin, curry powder, saffron and white pepper samples had levels ranging from 1 to 5 microg/kg. Aflotoxins were not detected in cardamon, cloves, ginger and mustard. None of the samples analysed contained aflatoxins B2, G1 and G2.

Aflatoxins↗

PubMed2003

Occurrence of aflatoxins in layer feed and corn samples in Konya province, Turkey.

The natural occurrence of aflatoxin was investigated in layer feed and corn samples brought to Konya Veterinary Control and Research Institute Laboratory between 15 April and 15 December 2002. Seventy-eight samples (52 feeds, 26 corn samples) were analysed for total aflatoxin (B1 + B2 + G1 + G2) by an ELISA screening method. Aflatoxin contamination was deter-mined in 37 feed samples (71.1%) and 15 corn samples (57.7%), with a range of 1.5-133 microg kg(-1). However, a majority of the aflatoxin contamination was less than 5 microg kg(-1) (50% within the positive samples). Two feed samples and two corn samples exceeded the maximum tolerated levels in feed (20 microg kg(-1)) and feedstuffs (50 microg kg(-1)) for total flatoxin.

Aflatoxins↗

PubMed2006

Aflatoxin B(1) contamination of parboiled rice samples collected from different states of India: A multi-centre study.

Under a multi-centre study conducted by the Indian Council of Medical Research, 1,511 samples of parboiled rice were collected from rural and urban areas of 11 states representing different geographical regions of India. These samples were analysed for contamination with aflatoxin B(1.) The presence of aflatoxin B(1) at levels=5 microg g(-1) was found in 38.5% of the total number of samples of the parboiled rice. About 17% of the total samples showed the presence of aflatoxin B(1) above the Indian regulatory limit of 30 microg kg(-1). No statistically significant difference in percentage of samples contaminated with >30 microg kg(-1) was observed between pooled rural (19.4%) and urban (14.5%) data. A median value of 15 microg kg(-1) of aflatoxin B(1) was observed in samples from Assam, Bihar and Tripura. In all other states surveyed the median value was <5 microg?kg(-1).

Aflatoxin B1↗