Biogenic amines are metabolic products that occur naturally in human, plant and animal cells. They are formed from the smallest building blocks of proteins, the amino acids (for example histidine). The group of biogenic amines includes histamine, tryamine, putrescine, cadaverine and phenylethylamine. They play an important role in human physiology. For example, histamine is involved in the regulation of various bodily functions such as gastric juice secretion, cell growth and differentiation, sleep-wake rhythm, learning and memory.
Biogenic amines can be increasingly produced during food processing through fermentation and ripening, but can also be formed during food spoilage by bacteria. On the one hand, they are aroma and flavor substances and participate in the browning of foods. On the other hand, they are used as a criterion in the quality control of foodstuffs, since elevated levels indicate spoilage.
Fermented foods such as raw sausage, anchovies, ripened cheeses and sauerkraut can contain particularly high amounts of biogenic amines, although the levels can vary greatly. But long storage and higher temperatures also promote the formation of biogenic amines, especially putrescine and cadaverine, in fresh foods such as leafy vegetables and mushrooms.
Histamine, tyramine and phenylethylamine are vasoactive, i.e. they have a vasoconstrictor or dilator effect, and in higher concentrations can affect blood pressure and cause headaches, allergy-like reactions such as hives (urticaria), and severe food poisoning.
Putrescine and cadaverine are often cited as potentiators of these effects. Particular amplification of these effects has been reported with concomitant consumption of alcohol or ingestion of drugs containing monoamine or diamine oxidase inhibitors.
The sensitivity of people to these contaminants varies widely and depends on many different factors, such as, most importantly, the enzymes available for degradation. Approximately 15% of the population has either a genetic or a drug-induced enzyme defect.
Situation in Austria
Biogenic amines in foods such as fish and cheese are investigated as part of official food control. For example, regular focus actions are carried out on histamine in tuna and tuna products.
In recent decades, it has been possible to reduce the levels of biogenic amines by identifying critical points of formation during production, the targeted use of starter cultures - these are specific microorganisms for fermentation in food production that form fewer amines - and improved methods of packaging, storage and transport.
So far, the EU has only set maximum levels for histamine in histidine-rich marine fish such as fish species of the families Scombridae, Clupeidae, Engraulidae, Coryfenidae, Pomatomidae and Scombraesosidae. There are no regulations for histamine or other biogenic amines in other foods.
Biogenic amines are organic bases with low molecular masses below 800 g/mol. Aromatic amines, such as tyramine and phenylethylamine, consist of hydrocarbon ring systems. Heterocyclic amines, such as histamine and tryptamine, have a ring-like structure whose ring skeleton contains at least one atom of another chemical element, e.g., nitrogen, in addition to carbon atoms. Aliphatic amines, such as putrescine and cadaverine, are compounds with one or more open hydrocarbon chains. We have conducted risk assessments on the biogenic amines histamine, tyramine, phenylethylamine, tryptamine, putrescine, and cadaverine. These each include an overview of published toxicologically effective levels and a summary of possible levels in various foods. Finally, in combination with Austrian consumption data, possible tolerable levels were derived for the individual biogenic amines in various fermented foods such as ripened cheese, sauerkraut, fish and raw sausage.
Histamine can cause intoxication when consumed in higher amounts (over 1000 mg histamine per meal) via histamine-rich foods, such as tuna, hard cheese, or red wine. This poisoning is characterized by an incubation period of a few minutes to hours, with symptoms that are usually noticeable for only a few hours. Symptoms of histamine poisoning include nausea, headache, shortness of breath, palpitations (tachycardia), cardiac arrhythmias (extrasystoles), drop in blood pressure (hypotension), swelling of the eyelids (edema), and hives (urticaria). In the EU, there are legal limits for histamine content only for certain marine fish, e.g. tuna. In the risk assessment, we propose tolerable levels for fermented sausage, fish and cheese. These were calculated by linking the amount of histamine at which no health effects are expected after ingestion to the amounts typically consumed of these foods. For fermented sausage and cheese, tolerable levels of 500 and 400 mg/kg, respectively, are acceptable. For fish species other than those already regulated in the EU, limits of 100 and 200 mg/kg can be adopted. These tolerable levels can be met using current food technology methods.
PUTRESCIN and CADAVERIN
Putrescine and cadaverine in foods may potentiate the effect of histamine ingested at the same time. In protein-rich foods, such as cheese, high concentrations of these two biogenic amines indicate hygienic deficiencies in food production. They are precursors for carcinogenic nitrosamines. Putrescine promotes cell division and also plays a role in tumor growth. So far, no tolerable levels have been established in food. In the risk assessment, we propose tolerable levels for cheese, fermented sausages, fish, sauerkraut and spices based on toxicological thresholds, occurrence in food and food consumption in Austria. For putrescine, maximum tolerable levels of 140, 170, 180, 360, and 510 mg/kg are proposed for sauerkraut, fish, cheese, fermented sausages, and spices, respectively. For cadaverine in sauerkraut, fish, cheese, fermented sausages and spices, the tolerable levels are 430, 510, 540, 1,080 and 1,540 mg/kg, respectively. These levels can be met by current manufacturing practices, as indicated by the results of our own studies and from the literature. However, few data have been published on toxicological thresholds for these two biogenic amines, so these tolerable levels are subject to considerable uncertainty.
Tyramine is one of the most important vasoactive amines in food, causing headache and an increase in systolic blood pressure. In the risk assessment, we propose risk-based tolerable levels of tyramine for certain foods. Dose-response data indicate that the highest dose at which no adverse effect is yet observed ("No Observed Adverse Effect Level" (NOAEL)) for healthy individuals is 200 mg per single oral dose. Based on this NOAEL and Austrian consumption data, the following maximum tolerable tyramine levels are suggested for foods: 1000 mg/kg for cheese; 2000 mg/kg for fermented and raw cured meat products; 950 mg/kg for fish (raw or processed); and 800 mg/kg for sauerkraut. Reduced bioavailability of amines when ingested with solid food was considered; sensitive consumers and interactions with other amines in foods were not considered. Literature data indicate that these tolerable levels may be exceeded in practice, at least for cheese. However, surveys of foods on the Austrian market show maximum tyramine levels well below the estimated tolerable levels. In the case of medication with monoaminooxidase inhibitors, the highest dose without an observed negative effect is significantly lower at 5 mg per meal; this can easily be exceeded under normal dietary conditions.
β-Phenylethylamine, along with the structurally related tyramine, is one of the most significant vasoactive amines present in foods. As symptoms of an excessive amount of ingested phenylethylamine, headache, dizziness, feeling of heat, nausea and an increase in systolic blood pressure can be observed. From the literature and our own studies, it appears that in solid foods, phenylethylamine concentrations above 100 mg/kg are found only in cheese. The published maximum levels in alcoholic beverages are below 25 mg/l. From literature data, it can be deduced that 5 mg per single oral administration represents the lowest dose at which an adverse effect can already be observed (Lowest Observed Adverse Effect Level). Based on Austrian consumption data, the following tolerable levels result under the assumption of high consumption: 25 mg/kg for cheese and fish; 50 mg/kg for raw sausage and chocolate; 70 mg/kg for seasoning sauces. For wine, taking into account an uncertainty factor of 10, a maximum level of 1 mg/l is derived. As the data from the literature and our own studies show, these tolerable levels in solid foods can certainly be observed.
Tryptamine acts in the human body on the nervous system (neuromodulator) and on the vessels (vasoactive). Effects similar to those of tyramine are expected, namely vasoconstriction, increase in blood pressure, headache, fever, sometimes vomiting and sweating. Tryptamine ingested with food is rapidly degraded by the enzyme monoamine oxidase. Dose-response data on dietary tryptamine are scarce. No toxicological threshold could be established. An oral dose without effect of 8 mg/kg body weight per day was derived from literature data. Dietary intake of tryptamine via fish and seafood, beer, cheese, and meat products was estimated for the Austrian population. Even worst-case estimates based on very high tryptamine levels reported in the literature did not exceed 5.9 mg/kg body weight and day, which was below the dose with no observed effect. For fish, canned fish, cheese, raw sausage, spices, sauerkraut, and fermented tofu, maximum tolerable levels of 1650, 3200, 2840, 4800, 14,120, 1740, and 2400 mg/kg, respectively, were derived. For beer, the maximum tolerable level of 65 mg/kg included an uncertainty factor of 10. None of the Austrian samples exceeded these levels. In fact, only 3.3% of the samples had measurable levels of tryptamine. Only one report was found in the literature of a raw fish sample exceeding the tolerable level. Dietary intake of tryptamine in healthy individuals should have no adverse health effects. The assessment did not consider the combined effects of simultaneously ingested biogenic amines and increased susceptibility to tryptamine, e.g., due to reduced monoamine oxidase activity.
WÜST N., RAUSCHER-GABERNIG E., STEINWIDER J., BAUER F., PAULSEN P. (2017): Risk assessment of dietary exposure to tryptamine for the Austrian population. Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 34(3): 404-420.
RAUSCHER-GABERNIG E., GABERNIG R., BRÜLLER W., GROSSGUT R., BAUER F., PAULSEN P. (2012): Dietary exposure assessment of putrescine and cadaverine and derivation of tolerable levels in selected foods consumed in Austria. European Food Research and Technology, published online May 17 2012; DOI 10.1007/s00217-012-1748-1.
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Last updated: 10.10.2023