Patulin is an organic compound that is classified as a polyketide. It is a white powder that is soluble in acidic water as well as in organic solvents. It is a lactone that is heat-stable, so it is not destroyed by pasteurization or thermal denaturation. However, stability following fermentation is lessened. It is a mycotoxin produced by a variety of molds, in particular, Aspergillus and Penicillium and Byssochlamys. Most commonly found in rotting apples, in general the amount of patulin in apple products is viewed as a measure of the quality of the apples used in production. In addition, patulin has been found in other foods such as grains, fruits, and vegetables. Its presence is highly regulated.
Biosynthesis, synthesis, and reactivity
The immediate precursor is 6-methylsalicylic acid. Isoepoxydon dehydrogenase is an important enzyme in the multi-step biosynthesis of patulin. Its gene is present in other fungi that may potentially produce the toxin. It is reactive with sulfur dioxide, so antioxidant and antimicrobial agents may be useful to destroy it. Levels of nitrogen, manganese, and pH as well as abundance of necessary enzymes regulate the biosynthetic pathway of patulin.
Uses
Patulin was originally used as an antibiotic against Gram-positive and Gram-negative bacteria, but after several toxicity reports, it is no longer used for that purpose. Isolated by Nancy Atkinson in 1943, it was specifically trialed to be used against the common cold. Patulin is used as a potassium-uptake inhibitor in laboratory applications. Kashif Jilani and co-workers reported that patulin stimulates suicidal erythrocyte death under physiological concentrations.
Toxicity
A subacute rodent NOAEL of 43 μg/kg body weight as well as genotoxicity studies were primarily the cause for setting limits for patulin exposure, although a range of other types of toxicity also exist. While not a particularly potent toxin, patulin is genotoxic. Some theorize that it may be a carcinogen, although animal studies have remained inconclusive. Patulin has shown antimicrobial properties against some microorganisms. Several countries have instituted patulin restrictions in apple products. The World Health Organization recommends a maximum concentration of 50 µg/L in apple juice. In the European Union, the limit is also set to 50 micrograms per kilogram in both apple juice and cider, and to half of that concentration, 25 µg/kg, in solid apple products and 10 µg/kg in products for infants and young children. These limits came into force on 1 November 2003.
Acute
Patulin is toxic primarily through affinity to sulfhydryl groups, which results in inhibition of enzymes. Oral LD50 in rodent models have ranged between 20 and 100 mg/kg. In poultry, the oral LD50 range was reported between 50–170 mg/kg. Other routes of exposure are more toxic, yet less likely to occur. Major acute toxicity findings include gastrointestinal problems, neurotoxicity, pulmonary congestion, and edema.
Subacute
Studies in rats showed decreased weight, and gastric, intestinal, and renal function changes, while repetitive doses lead to neurotoxicity. Reproductive toxicity in males were also reported. A NOAEL in rodents was observed at 43μg/kg bw.
Genotoxicity
concluded that patulin is genotoxic based on variable genotoxicity data, however it is considered a group 3 carcinogen by the International Agency for Research on Cancer, since data was inconclusive.
Reproduction studies
Patulin decreased sperm count and altered sperm morphology in the rat. Also, it resulted in abortion of F1 litters in rats and mice after i.p. injection. Embryotoxicity and teratogenicity were also reported in chick eggs.
Immunotoxicity
Patulin was found to be immunotoxic in a number of animal and even human studies. Reduced cytokine secretion, oxidative burst in macrophages, increased splenic T lymphocytes, and increased neutrophil numbers are a few endpoints noticed. However, dietary relevant exposure would not be likely to alter immune response.
Human health
Although there are only very few reported cases and epidemiological data, the FDA has set an action limit of 50 ppb in cider due to its potential carcinogenicity and other reported adverse effects. In humans, it was tested as an antibiotic intranasally for use against the common cold with few significant adverse effects, yet also had negligible or no beneficial effect.
Risk management and regulations
Patulin exposure can be successfully managed by following good agricultural practices such as removing mold, washing, and not using rotten or damaged apples for baking, canning, or juice production. US The provisional tolerable daily intake for patulin was set at 0.43 µg/kg bw by the FDA based on a NOAEL of 0.3 mg/kg bw per week. Monte Carlo analysis was done on apple juice to compare exposure and the PTDI. Without controls or an action limit, 90th percentile of consumers would not be above the PTDI. However, the concentration in children 1–2 years old would be 3 times higher than the PDTI. Hence, an action limit of 50 µg/kg was set. WHO The World Health Organization recommends a maximum concentration of 50 µg/L in apple juice. EU The European Union has set a maximum limits of 50μg/kg pertaining to fruit juices and drinks, while solid apple products have a limit of 25μg/kg. For certain foods intended for infants, and even lower limit of 10μg/kg is observed. To test for patulin contamination, a variety of methods and sample preparation methods have been employed including thin layer chromatography, gas chromatography, high-performance liquid chromatography, capillary electrophoresis.
