a Department of Seafood Processing Technology, Faculty of Fisheries, Cukurova University, Balcali, Adana, 01330, Turkey. E-mail: firstname.lastname@example.org
Biogenic amines (BAs) are important nitrogenous compounds formed mainly by decarboxylation of amino acids or by amination and transamination of aldehydes and ketones. In food and beverages, biogenic amines are formed by the enzymes of raw material and generated by microbial decarboxylation of amino acids. Therefore, the total amount and variety of amines strongly depend on the nature of the food and on the microorganisms present. Their presence is related to spoilage and fermentation processes. Toxicological characteristics of food poisoning are generally associated with histamine and tyramine. Other amines, such as putrescine, cadaverine, and phenylethylamine, are also important since they could intensify the undesirable effects of histamine. The other amines may form nitrosamines which are formed by the reaction of secondary or tertiary amines with a nitrosating agent. In foods, the nitrosating agent is usually nitrous anhydride and is produced from nitrite in acidic, aqueous solution. Thus, BAs are considered as a food hazard, although there is not a threshold for these biomolecules in European legislation, except for histamine in fishery products. When present in high concentrations, they could have toxicological effects, causing health problems in consumers, especially for sensitive individuals. Therefore, a better knowledge of BAs is important in order to improve the quality and safety of food. This chapter focuses on the basic information of BAs, including chemical structure, properties, their toxicology, and regulations on their levels in food for different countries.
Biogenic amines (BAs) are nitrogenous low molecular weight organic bases and they have an aliphatic, aromatic, or a heterocyclic structure. Biogenic amines are produced by the decarboxylation of their respective free precursor amino acids, through the catalytic action of substrate-specific microbial decarboxylases that remove the α-carboxyl group of amino acids to give the corresponding amines.1 They are present in a wide range of food products, including fish, fish products, meat products, eggs, cheeses, fermented vegetable, fruits, soybean products, beers, wines, nuts, and chocolate.2–5 The most significant biogenic amines occurring in foods are histamine (HIS), tyramine (TYR), putrescine (PUT), cadaverine (CAD), tryptamine (TRY), and β-phenethylamine (PHE) and they originate from the precursor amino acids histidine, tyrosine, ornithine, lysine, tryptophane, and phenylalanine, respectively. The demand for safer foods has led to more research into biogenic amines over the last decades. The presence of biogenic amines in these foods is associated with toxicological reason and quality indicators.6,7 Improper storage of food can lead to the formation of BAs. A majority of BAs are malodorous, toxic, and carcinogenic, causing dizziness, faintness, headaches, cardiac palpitations, mucosal burns, and irritation to the eyes etc.8,9 The purpose of this chapter is to provide basic information on BAs, including chemical structure, properties, their toxicology, and regulations on their levels in food for different countries.
α-Amino acids are basic units of proteins and they consist of α-carbon atom covalently attached to a hydrogen atom (H), an amino group (NH2), a carboxyl group (COOH), and a side-chain R group.
Amines are basic nitrogenous compounds in which one, two, or three atoms of hydrogen in ammonia are replaced by alkyl or aryl groups. The formation of these low molecular nitrogen compounds occurs through four enzymatic reactions: (i) decarboxylation, (ii) transamination, (iii) reductive amination, and (iv) degradation of certain precursor amino compounds.10 Decarboxylation of amino acid is the most common way of synthesis of amines in foods. Since these amines are formed by the action of living organisms by the decarboxylation process of amino acids, they are called biogenic. Amino acid decarboxylation occurs by removal of the α-carboxyl group to give the corresponding amine. The names of many biogenic amines correspond to the names of their originating amino acid; for instance, histamine from histidine, tyramine from tyrosine, agmatine from arginine, β-phenylethylamine from phenylethylalanine, and tryptamine from tryptophan (Figure 1.1). An alternative pathway for plants and some microorganisms takes place to form putrescine from arginine via agmatine. Lysine is decarboxylated by lysine decarboxylase to produce cadaverine, and it can also be produced by ornithine decarboxylase when the content of ornithine is low, but lysine content is high.11
The chemical structure of biogenic amines can be three forms: aliphatic (putrescine, cadaverine, spermine, and spermidine); aromatic (tyramine and phenylethylamine); heterocyclic (histamine and tryptamine). They can also be classified into monoamines (phenylethylamine and tyramine), diamines (cadaverine and putrescine), or polyamines (spermidine and spermine) based on the number of amine groups.12 Putrescine, spermidine, spermine, and cadaverine are essential components of living cells, regulating nucleic acid function, protein synthesis, and the stabilization of membranes.13 Dietary BAs are metabolized by acetylation and oxidation reactions enhanced by the enzymes monoamine oxidase (MAO) or diamine oxidase (DAO).14 Preconditions for biogenic amine formation by microorganisms are: (i) availability of free amino acids, (ii) presence of decarboxylase-positive microorganisms, and (iii) conditions that allow bacterial growth, decarboxylase synthesis, and decarboxylase activity.15
Proteolysis that occurs either autolytic or bacterial may play an important role in the release of free amino acids from tissue proteins which offer a substrate for decarboxylases reactions.2 It is reported that two mechanisms of reaction for amino acid decarboxylation take place, which is a pyridoxal phosphate dependent reaction and a non-pyridoxal phosphate dependent reaction.16
Biogenic amines are nitrogen sources and precursors for the synthesis of hormones, alkaloids, nucleic acids, and proteins. BAs have many important biological functions in the human nervous system (e.g. as neurotransmitter) and the cardiovascular system (controlling blood pressure), and play a significant role in the regulation of body temperature and digestion.2,17–19 BAs can be of endogenous origin at low concentrations in fresh food products. However, BAs presence in foods is closely associated with microbial activity. High level of BAs in food may be harmful to the nervous and cardiovascular systems of humans and also change food flavour. In addition, BAs are well known as potential precursors of carcinogenic nitrosamines.20
BAs can be used as spoilage indicators for different meat products. In particular, the biological amines index (BAI = histamine + putrescine + cadaverine + tyramine) and quality index (QI) = (histamine + putrescine + cadaverine)/(1 + spermidine + spermine) have been used to evaluate the freshness of meat products.21,22 BAs formation are species specific. Putrescine and cadaverine have been detected in significant concentrations in fermented meat and fish.23–25 Cadaverine was reported to be a reliable spoilage indicator of poultry meat,26,27 whereas histamine has been regarded as an index of the fish quality, particularly dark-muscle fish.28 Tyramine is reported to cause food intoxication commonly associated with ripened cheeses,29,30 affecting health due to its capacity to potentiate sympathetic cardiovascular activity by releasing noradrenaline, called “cheese reaction”.31 Histamine, putrescine, cadaverine, tyramine, 2-phenylethylamine, and tryptamine are often detected in fermented products.25,32 In addition, the level of BAs in alcoholic beverages (i.e. wine and beer) has received much attention since ethanol and acetaldehyde can increase the risk to human health by retarding the enzymes responsible for detoxification.33,34
Spermine and spermidine are mainly found bound to polyanionic molecules such as DNA, RNA, ATP, and phospholipids.35 They are involved in the regulation of cell growth and proliferation, in regulating DNA transcription, RNA translation, protein biosynthesis, the modulation of kinase activity, the activity of ion channels, apoptosis, and in adjusting the immune response.36–38 They play a role in the growth, maturation, and regeneration of intestinal cells, and possess potent antioxidant activity at physiological concentrations, preventing the damage of cell membranes and DNA.36 However, spermine and spermidine were reported to be harmful to health. In laboratory animals, the administration of spermine and spermidine resulted in an acute decrease in blood pressure, respiratory symptoms, and nephrotoxicity.36 They are also involved in carcinogenesis, tumour invasion, and metastasis.37 The catabolic enzyme spermine/spermidine N1-acetyltransferase, which reduces cell spermine and spermidine contents, also seems to reduce cell growth, migration, and invasion in hepatocellular carcinoma and colorectal cancer.39 Although high levels of spermine and spermidine are associated with these potential health risks, legal limits of spermine and spermidine in foods have not been established yet.
del Rio et al.40 reported that spermine or spermidine in food is not harmful to healthy people. However, patients with cancer are not advised to consume spermine/spermidine-rich foods.38 Patients with chronic kidney failure show high plasma polyamine oxidase activity, which causes an increase in spermine and spermidine catabolism and the accumulation of toxic acrolein. In such patients, a high polyamine (PA) might be harmful.41 In addition, under acidic conditions, spermidine reacts with nitrous acid preservatives in food, forming the nitrosamines N-nitrosopiperidine and N-nitrosodimethylamine, which are carcinogens.42
Cadaverine, putrescine, spermine, and spermidine have been classified within the group of polyamines. All of them are involved in DNA, RNA, and protein synthesis and they are necessary for normal growth, renovation, and metabolism of every organ in the body, as well as maintaining the metabolic activity of normal functions and the immunological system of the gut. Since polyamines are preferred by tissues with high demands, they could be beneficial for post-operation patients or wound healing, and the development of a neonate's digestive system.43 Polyamines have also been demonstrated to inhibit the oxidation of polyunsaturated fatty acids, and the antioxidative effect is related to the number of amine groups in the polyamine.11
Biogenic amines also play a role as neurotransmitters in physiological functions. They are synthesized in the nervous system and are divided into catecholamines, indoleamines, and imidazoleamines. It was indicated that psychoactive amines (dopamine and serotonin) are neurotransmitters in the central nervous system. Biogenic amines located in the central nervous system are crucial to life. A lack of these neurotransmitters can cause mental disorders, such as infantile autism, sleep disorders, depression, and Parkinson's disease.44–46 A better understanding of the conformational binding of those bio-active compounds in confined biological environments is essential in the treatment of those diseases.47 Determination of specific amine roles is difficult due to their complicated interactions and the complexity of the nervous system. Thus, many amine functions have not been completely explained.48 Biogenic amines, such as tyramine and β-phenylethylamine, have been proposed as the initiators of a hypertensive crisis in certain patients and of dietary-induced migraines.49 Tyramine and histamine also act as hormonal mediators in humans and animals.
Histamine poisoning is a foodborne chemical intoxication caused by the ingestion of foods containing high amounts of histamine. Histamine fish poisoning, also known as scombroid poisoning, is the most common cause of ichythyotoxicosis worldwide. This disease was first described in 1799 in Britain and re-emerged in the medical literature in the 1950s when outbreaks were recorded in Japan.47 Although commonly associated with the consumption of scombroid-type fish, other foods such as cheese have also been associated with outbreaks of histamine poisoning. The term “scombroid” derives from a type of fish (i.e. Scombridae) such as tuna and mackerel. Scombrid fish are characterized by high levels of free histidine in their muscle tissues.50 Other (non-scombroid) fish species are also reported in scombroid poisoning, including anchovies, yellowtail steak, mahi-mahi, tuna, herring, and sardine bluefish, and fish products such as sauce and dried fish.51–55 These species have relatively high levels of histidine in their flesh.8,54 Histidine levels range from 1 g kg−1 in herring to 15 g kg−1 in tuna.56 Fresh fish contains negligible quantities of histamine, usually <0.1 mg per 100 g.57 Scombroid poisoning results from consumption of mishandled fish. Histamine (2-(1H-imidazol-4-yl) ethanamine) and other decomposition products are produced in raw fish by bacterial, enzymatic conversion of free histidine. Figure 1.2 shows a schematic summary of histamine poisoning in food.
The metabolism of histidine basically follows two ways: the major route of catabolism of histidine passes through its transformation to glutamic acid, which begins with the degradation of histidine to urocanic acid by action of the enzyme histidase. The glutamate product is converted to α-ketoglutarate, which is an intermediate in the citric acid cycle (Krebs cycle). The second is the decarboxylation (loss COO–) for action of the enzyme histidine decarboxylase with formation of histamine.58 The process of decarboxylation is initiated mainly by enzymes produced by gram-negative enteric bacteria such as Morganella morganii, Escherichia coli, Klebsiella spp., and Pseudomonas aeruginosa which are found in the intestine and skin of the fish.59 These bacteria are present in the marine environment and also in the intestine and gills of the fish, causing no disease. Bacteria capable of amine production include Escherichia, Enterobacter, Salmonella, Shigella, Streptococcus, Lactobacillus, Leuconostoc spp., and Clostridium perfringens.60 To prevent poisoning, the fish should be iced during the food chain until consumption. If the preservation techniques are not good, the degradation of histidine to histamine can occur due to bacteria growth. Storage temperature is the most important factor controlling BAs formation.61 Other parameters such as pH, water activity, NaCl concentration, and additives may affect microbiota composition and result in differences in BAs content.62
Fermented foods such as wine, dry sausage, sauerkraut, miso, and soy sauce can also contain histamine along with other biogenic amines. Microorganisms with histidine decarboxylase enzyme, which converts histidine to histamine, are responsible for the formation of histamine in foods. The toxicity of histamine is enhanced by the presence of other biogenic amines (putrescine and cadaverine) in foods, inhibiting histamine-metabolizing enzymes in the intestine.49 DAO is the major histamine catabolizing enzyme in the intestinal tract. The hypersensitivity to histamine could occur due to DAO deficiency or the use of drugs which are DAO inhibitors (DAOI), such as clavulanic acid, verapamil, acetylcysteine, and metoclopramide.63 The consumption of products with histamine could cause adverse effects in a person treated with DAOI. Therefore, sensitive individuals should avoid the consumption of foods such as dry fermented sausages, cheese, wine, and fish products that are also potential sources of biogenic amines.64
Estimating occurrence of histamine poisoning is hard because most countries do not regulate histamine levels in foods and they do not require warning when an incident of histamine poisoning takes place. In addition to this, histamine poisoning induces allergy-like symptoms which closely resembles a food allergy.65 Thus, it may often be misdiagnosed.
Ohnuma et al.66 categorized the symptoms as follows: Skin: Rash, urticaria, localized swelling, and erythema on the face, neck, and trunk. Gastrointestinal system: Nausea, vomiting, diarrhoea, epigastric pain, and cramping. Circulatory system: Conjunctival injection, hypotension or hypertension, tachycardia, and palpitations, up to shock. Nervous system: Headache, tingling, cramps, feeling of warmth around the mouth, and loss of sight. Respiratory system: Bronchoconstriction and respiratory distress.
The onset of the symptoms generally occurs within a few minutes after ingestion of the implicated food, and the duration of symptoms ranges from a few hours to 24 h. More severe symptoms (e.g. respiratory distress, swelling of the tongue and throat, and blurred vision) can occur and require medical treatment with antihistamines. The United States Federal Drug Administration (FDA) and the European Union (EU) suggest that safe levels of histamine in fish meat should not exceed 50 ppm and 100 ppm, respectively.67,68 The New Zealand cut-off is 200 mg kg−1 in fish or fish products, which is the same as in South Korea. When histamine levels exceed these standards in fish or fish products before shipment or distribution, they are discarded. The only effective method for prevention of scombroid fish poisoning is consistent temperature control of fish at 4.4 °C between catching and consumption.69 The bacterial spoilage and the production of histamine can occur at any stage of the food chain such as fishing and fish landing, processing, distribution systems, as caterers, or at home. The rapid cooling of the fish and a maintenance of the cold chain until the consumption of the product are very important to avoid bacterial proliferation, activation of the enzyme histidine decarboxylase, and the conversion of histidine to histamine. In future, scombroid outbreaks can be prevented if fishermen, public health officials, workers in restaurant, and medical professionals work together to set international safety standards and increase awareness of this poisoning.
After fish, fermented meats, vegetables, dairy products, and alcoholic beverages may accumulate high levels of histamine.6,70 In some types of cheese, histamine can even exceed 1000 mg kg−1, causing histamine poisoning.71 In spite of the cold chain, cheeses with high concentrations of histamine are on the market.72,73 Although a number of microorganisms in cheese, including moulds, yeasts, and Gram-negative bacteria, are able to produce histamine,74 lactic acid bacteria (LAB), which produce histidine decarboxylase enzyme, are thought to be mainly responsible for histamine accumulation.71,75 LAB may form the milk microbiota, or can be introduced by contamination before, during, or after processing, or may even be part of the starter culture. Diaz et al.76 reported that Lactobacillus parabuchneri, responsible for histamine accumulation in cheese, can grow and produce histamine at 4 and 8 °C. Moreover, L. parabuchneri produced toxic histamine concentrations in refrigerated cheeses from only 14 days. Thus, refrigeration delays but does not prevent the accumulation of toxic histamine levels in cheese.
Fermented dairy products, especially cheese, are the main sources of biogenic amines, mainly histamine, tyramine, putrescine, and cadaverine. Many factors have been reported to affect the production of biogenic amines in cheeses, including the presence of microorganisms decarboxylating free amino acids, the presence of spoilage microorganisms, and the synergistic effects of microorganisms and free amino acids as an outcome of proteolysis levels.77,78 In addition, pH, salt-in-moisture levels, and ripening temperature also play an important role.79,80 Since the content of BAs is influenced by ripening and quality of storage conditions, attention in the amount of BAs in food is always being paid, not only due to the potential toxicity but also being a parameter for ripening and the quality of storage. TYR is produced from amino acid tyrosine by tyrosine decarboxylase enzyme and metabolized by monoamine oxidase. It is also present in many foods and beverages such as meat, fish and fish products, alcoholic beverages, and dairy products.81 TYR is the major biogenic amine in cheese and is responsible for the “cheese effect” which is characterized by hypertension, headache, and migraine. It was also reported that TYR can cause necrosis of human intestinal cells and this cytotoxicity was even stronger than that of histamine.6 Normally, ingested TYR does not have any adverse effects on human health since the intestinal wall and liver include monoamine oxidase, an enzyme metabolizing the TYR to less active p-hydroxylphenylacetic acid before being involved in the general circulation. On the other hand, when ingested in high amounts in food or in patients treated with monoamine oxidase inhibitor drugs, TYR cannot be detoxified adequately and passes into the circulation, resulting in the release of noradrenaline from the nervous system.82 TYR reacts with monoamine oxidase inhibitor (MAOI) drugs causing a hypertensive crisis.2 The enzyme, monoamine oxidase, oxidatively deaminates amines derived from food and plays a role in their degradation before they reach the blood. The use of MAOI drugs for treatment of mental depression eliminates this detoxification process and a high concentration of tyramine can be accumulated in the blood resulting in a hypertensive crisis for the patient.83 Halasz et al.84 reported that high intake of TYR can cause adverse toxicological effects and diseases such as high blood pressure, brain haemorrhage, palpitations, nausea, and diarrhoea.
In general, histamine and tyramine are thought to be the main cause of numerous cases of food intoxication.85 Putrescine and cadaverine have been reported as potentiators of toxic effect of other amines due to the inhibition of detoxifying enzymes.2,86 People with a lack of natural mechanisms for detoxifying BAs caused by genetic reasons and taking antidepressant medicines show that they are more sensitive to BAs poisoning.28 The toxicological level of BAs is very difficult to set as it depends on individual characteristics and the presence of other amines. However, a maximum total BAs level of 750–900 mg kg−1 has been proposed by Ladero et al.87
Histamine poisoning is concerned with public health and safety issues, and also the global fish trade.88 Processing methods such as cooking, canning, or freezing cannot eliminate histamine because it is heat stable.89 Therefore, it is important to accurately determine its level in fish and fish products.
According to Bartholomew et al.,90 levels of histamine poisoning are as follows: <5 mg of histamine per 100 g of fish: safe, 5–10 mg of histamine per 100 g of fish: possibly toxic, 20–100 mg of histamine per 100 g of fish: probably toxic, >100 mg of histamine per 100 g of fish: toxic.
The FDA in 1996 executed the Hazard Analysis and Critical Control Point (HACCP) program to prevent seafood processing hazards which cause foodborne illness. The level of 50 mg kg−1 was established for scombroid or scombroid-like fish at the port. According to Commission Regulation EC No 2073/2005 (Regulation 2073/2005/EC),91 the limit for histamine was established in fish species with a high amount of histidine, including families of Scombridae, Scombresosidae, Clupeidae, Engraulidae, Coryfenidae, and Pomatomidae, both fresh and treated by enzyme maturation in brine. Regulatory limits set by European legislation are a maximum of 200 mg kg−1 in fresh fish and 400 mg kg−1 in fishery products treated by enzyme maturation in brine. According to Codex Alimentarius, the histamine level in fish and fish products is 200 mg kg−1. Brazil and Mercosur limit histamine to 100 mg kg−189,92,93 whereas European regulation limits histamine content in fish and fish products to 100 and 200 mg kg−1.94
The main aim of the guideline established by the FDA89 is to inhibit the growth of spoilage bacteria which produce histamine during the handling and chilling of fish. There are a number of factors for time required to decrease the internal temperature of fish after capture, including the harvest and chilling methods, as well as fish size. The scombrotoxin-forming fish should be stored as close as possible to the freezing point until it is consumed.
Tao et al.54 determined histamine content in fresh scombroid fish (tuna, mackerel etc.) and non-scombroid fish (mahi–mahi, sardine, herring etc.), and fish products (sauce, dried fish) from Fiji, Germany, the Netherlands, Norway, Thailand, Cambodia, the Philippines, Japan, and China. Low level of histamine (12–31 ppm) was found in Fiji's fish samples. Histamine was determined in 2 of 12 samples from Germany (184 ppm in sardine and 68 ppm in herring). These concentrations were higher than the FDA regulation of 50 ppm histamine. Histamine was found in two of nine samples from the Netherlands (39 ppm in horse mackerel and 1439 ppm in tuna). Histamine level in the tuna (1439 ppm) exceeded the EC regulation of histamine (100 ppm–200 ppm) from the Netherlands although the tuna meat appeared to very fresh at that time. Histamine was found in 4 of 11 fish samples from Thailand in the range of 56 ppm and 1964 ppm. Histamine was determined in the three dried freshwater fish samples from Cambodia in the range of 25–148 ppm. Histamine was detected in 60% of the dried bonito samples from the Philippines and its level was in the range of 19 ppm to 1530 ppm. Histamine and biogenic amines were not detected in the samples from Japan. Histamine of 15 ppm was found in one sample from China. Putrescine (13–25 ppm) was detected in two samples (horse mackerel and saury), also cadaverine (6 ppm) was detected in one sample of horse mackerel. There is a need for monitoring of histamine to ensure the safety of commercial fish products in the world's fish markets.
Evaluation of alimentary exposure of consumers to individual biogenic amines and also maximum tolerable levels of these biogenic amines in different foods were carried out. For instance, Poulsen et al.95 estimated maximum tolerable levels of tyramine in foods in Austria. They reported that for individuals with no susceptibility to tyramine, it is reasonable to suggest a NOAEL (no observed adverse effect level) of 200 mg tyramine per meal. Maximum tolerable tyramine levels in cheese, fermented sausage, fish/fishery products, and sauerkraut could be 1000 mg kg−1, 2000 mg kg−1, 950 mg kg−1, and 800 mg kg−1, respectively. It was reported that normal consumption of tyramine is 100–800 mg kg−1 whereas levels higher than 1080 mg kg−1 are regarded as toxic. However, individuals under MAOI treatment are more sensitive to tyramine consumption and values of 60 mg kg−1 in the diet could cause a mild crisis, while 100–250 mg kg−1 is associated with severe headache with intracranial haemorrhage and sequelae.96
Due to the rapid metabolism of tryptamine, acute effects after oral intake are the main concern. Tryptamine contents in foods are in the range of a few mg kg−1 or lower.97 The highest reported tryptamine value in the EFSA Scientific Opinion was 362 mg kg−1 in fish and fish products and 10.1 mg kg−1 in fermented fish meat.98 The highest reported tryptamine level in cheese in the EFSA Scientific Opinion, which summarized data of over 2000 cheese samples from Europe, and in an Austrian semi-hard cheese, was 312 mg kg−1 However, 4% of the total EFSA's cheese samples gave a tryptamine level above the limit of detection (LOD).98,99 In a study by Wüst et al.,97 dietary exposure through fish/seafood, beer, cheese, and meat products was estimated for Austrian consumers, based on 543 food samples. For fresh/cooked fish, preserved fish, cheese, raw sausage, condiments, sauerkraut, and fermented tofu, maximum tolerable levels were found as 1650, 3200, 2840, 4800, 14 120, 1740, and 2400 mg kg−1, respectively. For raw sausages and beer, tryptamine contents were below the proposed maximum tolerable tryptamine level. Although they did not take into account combined effects of ingested biogenic amines and increased susceptibility to tryptamine, e.g. due to reduced MAO activity, they concluded that dietary intake of tryptamine should not result in adverse effects on healthy individuals.
The physicochemical control of six Italian-type salami brands sold in the city of Niteroi was evaluated by dos Santos et al.100 (Rio de Janeiro, Brazil). The quality control of salami should be essential, particularly moisture and protein contents since only half of the brands met the requirements of Brazilian law. Two brands presented histamine contents above the legal limit (100 mg kg−1). They concluded that the levels of biogenic amines found would cause an adverse effect in sensitive consumers, which depends on the amount and frequency of the intake of these products. Rauscher-Gabernig et al.101 suggested tolerable levels for putrescine and cadaverine in cheese, fermented sausages, fish, sauerkraut, and seasonings based on toxicological information and consumption habits in Austria. For putrescine, proposed maximum tolerable levels for sauerkraut, fish, cheese, fermented sausages, and seasonings are 140, 170, 180, 360, and 510 mg kg−1, respectively, whereas for cadaverine, maximum tolerable levels are 430, 510, 540, 1080, and 1540 mg kg−1, respectively in sauerkraut, fish, cheese, fermented sausages, and seasonings. In addition, studies showed that tyramine and histamine have synergistic cytotoxicity towards intestinal cell cultures. It was also indicated that histamine, below the legal limit, can raise the cytotoxicity of tyramine at a concentration frequently present in foods.6,40
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