Patulin is an

organic compound In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen or carbon-carbon bonds. Due to carbon's ability to catenate (form chains with other carbon atoms), millions of organic compounds are known. The ...

classified as a

polyketide Polyketides are a class of natural products derived from a precursor molecule consisting of a chain of alternating ketone (or reduced forms of a ketone) and methylene groups: (-CO-CH2-). First studied in the early 20th century, discovery, biosynth ...

. It is a white powder soluble in acidic water and in

organic solvent A solvent (s) (from the Latin '' solvō'', "loosen, untie, solve") is a substance that dissolves a solute, resulting in a solution. A solvent is usually a liquid but can also be a solid, a gas, or a supercritical fluid. Water is a solvent for p ...

s. It is a

lactone Lactones are cyclic carboxylic esters, containing a 1-oxacycloalkan-2-one structure (), or analogues having unsaturation or heteroatoms replacing one or more carbon atoms of the ring. Lactones are formed by intramolecular esterification of the co ...

that is heat-stable, so it is not destroyed by

pasteurization Pasteurization or pasteurisation is a process of food preservation in which packaged and non-packaged foods (such as milk and fruit juices) are treated with mild heat, usually to less than , to eliminate pathogens and extend shelf life. The ...

or thermal denaturation.http://www.sigmaaldrich.com/catalog/product/sigma/p1639?lang=en®ion=US However, stability following

fermentation Fermentation is a metabolic process that produces chemical changes in organic substrates through the action of enzymes. In biochemistry, it is narrowly defined as the extraction of energy from carbohydrates in the absence of oxygen. In food ...

is lessened. It is a

mycotoxin A mycotoxin (from the Greek μύκης , "fungus" and τοξίνη , "toxin") is a toxic secondary metabolite produced by organisms of kingdom Fungi and is capable of causing disease and death in both humans and other animals. The term 'mycotoxin' ...

produced by a variety of molds, in particular, ''

Aspergillus ' () is a genus consisting of several hundred mold species found in various climates worldwide. ''Aspergillus'' was first catalogued in 1729 by the Italian priest and biologist Pier Antonio Micheli. Viewing the fungi under a microscope, Miche ...

'' and ''

Penicillium ''Penicillium'' () is a genus of ascomycetous fungi that is part of the mycobiome of many species and is of major importance in the natural environment, in food spoilage, and in food and drug production. Some members of the genus produce pe ...

'' and '' Byssochlamys''. Most commonly found in rotting

apples An apple is an edible fruit produced by an apple tree (''Malus domestica''). Apple fruit tree, trees are agriculture, cultivated worldwide and are the most widely grown species in the genus ''Malus''. The tree originated in Central Asia, wh ...

, the amount of patulin in apple products is generally 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 (IDH) is an important

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...

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 Sulfur dioxide (IUPAC-recommended spelling) or sulphur dioxide (traditional Commonwealth English) is the chemical compound with the formula . It is a toxic gas responsible for the odor of burnt matches. It is released naturally by volcanic activ ...

, so antioxidant and antimicrobial agents may be useful to destroy it.Llewellyn, G.C.; McCay, J.A.; Brown, R.D.; Musgrove, D.L.; Butterworth, L.F.; Munson, A.E.; White, K.L., Jr. Immunological evaluation of the mycotoxin patulin in female B6C3F1 mice. ''Food Chem. Toxicol''. 1998, 36, 1107–1111. 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.Medical Research Council. Clinical trial of patulin in the common cold. ''Lancet''1944; ii: 373-5. Isolated by

Nancy Atkinson Nancy Atkinson, (also known as Nancy Cook and Nancy Benko; 9 March 1910 – 21 December 1999) was an Australian bacteriologist. In the 1950s, she was recognised as one of the world's leading authorities on bacteriology, and led research on '' Sa ...

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 Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek ''erythros'' for "red" and ''kytos'' for "holl ...

death under physiological concentrations.

Sources of exposure

Frequently, patulin is found in apples and apple products such as juices, jams, and ciders. It has also been detected in other fruits including cherries, blueberries, plums, bananas, strawberries, and grapes. Fungal growth leading to patulin production is most common on damaged fruits. Patulin has also been detected in grains like barley, wheat, corn and their processed products as well as in shellfish.,Pouchous et al. Shellfish Dietary intake of patulin from apple juice has been estimated at between 0.03 and 0.26 μg/kg bw/day in various age groups and populations.Wouters, FA, and Speijers, GJA. JECFA Monograph on Patulin. World Health Organization Food Additives Series 35 (http://www.inchem.org/documents/jecfa/jecmono/v26je10.htm) Content of patulin in apple juice is estimated to be less than 10–15μg/L. A number of studies have looked into comparisons of organic vs conventional harvest of apples and levels of patulin contamination. For example, one study showed 0.9% of children drinking organic apple juice exceeded the

tolerable daily intake Tolerable daily intake (TDI) refers to the daily amount of a chemical that has been assessed safe for human being on long-term basis (usually whole lifetime). Originally acceptable daily intake (ADI) was introduced in 1961 to define the daily intake ...

(TDI) for patulin. A recent article described detection of patulin in marine strains of Penicillium, indicating a potential risk in shellfish consumption.

Toxicity

A subacute rodent

NOAEL The no-observed-adverse-effect level (NOAEL) denotes the level of exposure of an organism, found by experiment or observation, at which there is no biologically or statistically significant increase in the frequency or severity of any adverse effec ...

of 43 μg/kg body weight as well as

genotoxicity Genotoxicity is the property of chemical agents that damage the genetic information within a cell causing mutations, which may lead to cancer. While genotoxicity is often confused with mutagenicity, all mutagens are genotoxic, but some genotoxic sub ...

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 Genotoxicity is the property of chemical agents that damage the genetic information within a cell causing mutations, which may lead to cancer. While genotoxicity is often confused with Mutagen, mutagenicity, all mutagens are genotoxic, but some geno ...

. 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 The World Health Organization (WHO) is a specialized agency of the United Nations responsible for international public health. The WHO Constitution states its main objective as "the attainment by all peoples of the highest possible level of h ...

recommends a maximum concentration of 50 µg/L in apple juice."Foodborne hazards (World Health Organization". Retrieved 2007-01-22. In the European Union, the limit is also set at 50 micrograms per kilogram (µg/kg) in apple juice and cider, at 25 µg/kg in solid apple products, and at 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 (SH), 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 and 170 mg/kg. Other routes of exposure are more toxic, yet less likely to occur. Major acute toxicity findings include gastrointestinal problems,

neurotoxicity Neurotoxicity is a form of toxicity in which a biological, chemical, or physical agent produces an adverse effect on the structure or function of the central and/or peripheral nervous system. It occurs when exposure to a substance – specificall ...

(i.e. convulsions),

pulmonary congestion Pulmonary edema, also known as pulmonary congestion, is excessive liquid accumulation in the tissue and air spaces (usually alveoli) of the lungs. It leads to impaired gas exchange and may cause hypoxemia and respiratory failure. It is due t ...

, and

edema Edema, also spelled oedema, and also known as fluid retention, dropsy, hydropsy and swelling, is the build-up of fluid in the body's Tissue (biology), tissue. Most commonly, the legs or arms are affected. Symptoms may include skin which feels t ...

Subacute

Studies in rats showed decreased weight, and gastric, intestinal, and renal function changes, while repetitive doses lead to neurotoxicity. Reproductive toxicity in males was also reported. A

in rodents was observed at 43μg/kg bw.

Genotoxicity

WHO Who or WHO may refer to: * Who (pronoun), an interrogative or relative pronoun * Who?, one of the Five Ws in journalism * World Health Organization Arts and entertainment Fictional characters * Who, a creature in the Dr. Seuss book '' Horton He ...

concluded that patulin is genotoxic based on variable

data, however it is considered a group 3 carcinogen by the

International Agency for Research on Cancer The International Agency for Research on Cancer (IARC; french: Centre International de Recherche sur le Cancer, CIRC) is an intergovernmental agency forming part of the World Health Organization of the United Nations. Its role is to conduct and ...

(IARC) 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 Teratology is the study of abnormalities of physiological development in organisms during their life span. It is a sub-discipline in medical genetics which focuses on the classification of congenital abnormalities in dysmorphology. The related t ...

were also reported in chick eggs.

Immunotoxicity

Patulin was found to be

immunotoxic An immunotoxin is an artificial protein consisting of a targeting portion linked to a toxin. When the protein binds to that cell, it is taken in through endocytosis, and the toxin kills the cell. They are used for the treatment of some kinds of c ...

in a number of animal and even human studies. Reduced cytokine secretion, oxidative burst in macrophages, increased splenic

T lymphocytes A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell rec ...

, and increased

neutrophil Neutrophils (also known as neutrocytes or heterophils) are the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. They form an essential part of the innate immune system, with their functions varying in ...

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 The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...

has set an action limit of 50 ppb in cider due to its potential

carcinogenicity A carcinogen is any substance, radionuclide, or radiation that promotes carcinogenesis (the formation of cancer). This may be due to the ability to damage the genome or to the disruption of cellular metabolic processes. Several radioactive subs ...

and other reported adverse effects. In humans, it was tested as an

antibiotic An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and prevention of ...

intranasally for use against the

common cold The common cold or the cold is a viral infectious disease of the upper respiratory tract that primarily affects the respiratory mucosa of the nose, throat, sinuses, and larynx. Signs and symptoms may appear fewer than two days after exposu ...

with few significant

adverse effect An adverse effect is an undesired harmful effect resulting from a medication or other intervention, such as surgery. An adverse effect may be termed a "side effect", when judged to be secondary to a main or therapeutic effect. The term complica ...

s, yet also had negligible or no beneficial effect.

Risk management and regulations

Patulin exposure can be successfully managed by following

good agricultural practices Good agricultural practice (GAP) is a certification system for agriculture, specifying procedures (and attendant documentation) that must be implemented to create food for consumers or further processing that is safe and wholesome, using sustaina ...

such as removing mold, washing, and not using rotten or damaged apples for baking, canning, or juice production. US The provisional

(PTDI) for patulin was set at 0.43 µg/kg bw by the FDA based on a

of 0.3 mg/kg bw per week.

Monte Carlo analysis Monte Carlo methods, or Monte Carlo experiments, are a broad class of computational algorithms that rely on repeated random sampling to obtain numerical results. The underlying concept is to use randomness to solve problems that might be determini ...

was done on apple juice to compare exposure and the PTDI. Without controls or an action limit, the 90th percentile of consumers would not be above the PTDI. However, the concentration in children 1–2 years old would be three times as high as the PDTI, hence an action limit of 50 µg/kg. WHO The

recommends a maximum concentration of 50 µg/L in apple juice. EU The

European Union The European Union (EU) is a supranational political and economic union of member states that are located primarily in Europe. The union has a total area of and an estimated total population of about 447million. The EU has often been des ...

(EU) has set a maximum limit of 50μg/kg on fruit juices and drinks, while solid apple products have a limit of 25μg/kg. For certain foods intended for infants, an 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 Thin-layer chromatography (TLC) is a chromatography technique used to separate non-volatile mixtures. Thin-layer chromatography is performed on a sheet of an inert substrate such as glass, plastic, or aluminium foil, which is coated with a t ...

(TLC),

gas chromatography Gas chromatography (GC) is a common type of chromatography used in analytical chemistry for separating and analyzing compounds that can be vaporized without decomposition. Typical uses of GC include testing the purity of a particular substance, ...

(GC),

high-performance liquid chromatography High-performance liquid chromatography (HPLC), formerly referred to as high-pressure liquid chromatography, is a technique in analytical chemistry used to separate, identify, and quantify each component in a mixture. It relies on pumps to pa ...

(HPLC), and

capillary electrophoresis Capillary electrophoresis (CE) is a family of electrokinetic separation methods performed in submillimeter diameter capillaries and in micro- and nanofluidic channels. Very often, CE refers to capillary zone electrophoresis (CZE), but other electr ...

.Variability and uncertainty assessment of patulin exposure for preschool children in Flanders

References

External links

Patulin
{{Webarchive, url=https://web.archive.org/web/20171219144226/http://www.foodsafetywatch.org/factsheets/patulin/ , date=2017-12-19 , Food Safety Watch Mycotoxins Furanones