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5.1.2 Production of biogenic amines (Lahsen Ababouch/Lone Gram)

a) the disease and some epidemiological aspects

Histamine poisoning is a food-borne chemical intoxication occurring few minutes to several hours following the ingestion of foods that contain unusually high levels of histamine (Taylor 1983, 1986).

It is usually a mild disorder with a variety of symptoms. The primary symptoms are cutaneous (rash, urticaria, oedema, localized inflammation), gastrointestinal (nausea, vomiting, diarrhoea), haemodynamic (hypotension) and neurological (headache, tingling, oral burning and blistering sensation, flushing and perspiration, itching). More serious complications such as cardiac palpitations are rare. The toxicity of histamine is probably potentiated by other biogenic amines (Taylor, 1986; Lehane and Olley, 2000).

Histamine poisoning occurs throughout the world and is perhaps the most common form of toxicity caused by the ingestion of fish (see Tables 4.3 and 4.5). However, good statistics about its incidence do not exist because the poisoning incidents are often unreported due to the mild nature of the illness, to lack of adequate system for reporting food-borne diseases or ignorance by medical personnel who misdiagnose histamine poisoning as a food allergy (Taylor, 1986; Lehane and Olley, 2000). Japan, the USA and the UK are the countries with the highest number of reported incidents, although this possibly implies better reporting on their part. Less frequent incidents have been reported elsewhere in Europe, Asia, Africa, Canada, New Zealand and Australia (Ababouch, 1991; Lehane and Olley, 2000).

Despite its toxicity, histamine is not a substance foreign to the human body. It is stored in specialized cells where its release is regulated. In small physiological doses, histamine is a necessary and desirable substance involved in the regulation of such critical functions as the release of stomach acid. But in large doses, histamine becomes toxic and can precipitate poisoning symptoms.

Although compelling evidence exists for the involvement of histamine as the causative agent of histamine food poisoning, it has been virtually impossible to reproduce the illness in oral challenge studies with human volunteers. The paradox between the lack of toxicity of pure histamine and the apparent toxicity of even smaller doses of histamine in spoiled fish has been attributed to the possible occurrence of histamine toxicity potentiators in the spoiled fish. Other biogenic amines (agmatine, putrescine, cadaverine, anserine, spermine and spermidine) trimethylamine or trimethylamine oxide have been suggested as potentiators (Taylor, 1986). Three theories have been advanced to explain the mechanism of histamine toxicity potentiation.

There is uncertainty regarding the threshold toxic concentration because potentiators of toxicity may be present in fish and lower the effective dosage compared with pure histamine. Different fish could contain different potentiators, and the levels of potentiators could also vary considerably from one fish to another.

Simidu and Hibiki (1955) estimated the threshold toxic dose for histamine in fish at approximately 60 mg/100g (600 ppm). Shalaby (1996) reviewed the oral toxicity to humans of histamine and other biogenic amines in foods. He considered that histamine-induced poisoning is, in general, slight at 8-40 mg/100g, moderate at >40 mg/100g and severe at >100 mg/100g. Based on an analysis of recent poisoning episodes, Shalaby (1996) suggested the following guideline levels for histamine content of fish:

b) prevalence in fish and fishery products

Biogenic amines are produced in foods by decarboxylation of the corresponding free amino acid (Table 5.17). This decarboxylation reaction is catalyzed by bacterial amino acid decarboxylases. Figure 5.5 represents the decarboxylation of histidine into histamine.

Table 5.17 Amino acid precursors and biogenic amines formed in food products.

Amino acid precursor

Biogenic amine













1. Not an amino acid

Histamine poisoning is often referred to as scombrotoxin poisoning because of the frequent association of the illness with the consumption of spoiled scombroid fish such as tuna (Thunnus spp.), skipjack (Katsuwonus pelamis), saury (Kololabis saira), bonito (Sarda spp.) and mackerel (Scomber spp.). However, non-scombroid fish such as sardines (Sardinella spp.), herring (Clupea spp.), pilchards (Sardina pilchardus), anchovies (Engraulis spp.), marlin (Makaira spp.), bluefish (Pomatomus spp.) and mahi-mahi (Coryphaena spp.) have also been implicated in outbreaks of this illness (Taylor, 1986; Lehane and Olley, 2000). More recent reports indicate the implication of salmon (Arripis truttaceus, Oncorrhynchus nerka) as well (Lehane and Olley, 2000).

Figure 5.5
Formation of histamine.

Many of these fish species have significant amounts of histidine in their muscle tissues that serves as a substrate for bacterial histidine decarboxylase. Free histidine is generally found in large amounts in the muscle of fatty, red-meat active and migratory species as compared to its amount in the white meat of slower species. The level of other amino acids, precursors of biogenic amines (Table 5.17) has not been sufficiently studied.

c) growth of biogenic amine forming bacteria and stability of toxin in fish products

Most studies have investigated histidine decarboxylation into histamine, whereas fewer reports exists on production of other biogenic amines (Flick et al., 2001).

In some studies (Taylor, 1986; Middlebrooks et al,. 1988), the potential for histamine and biogenic amines formation was evaluated by measuring the decarboxylase activity. This is not always appropriate as it ignores the role of histaminase for example, which has been found in some bacterial species (Taylor, 1986). Therefore, measurement of the actual amines must be done.

In general, the amino acid decarboxylase enzymes, especially histidine decarboxylase, can be found in species of Enterobacteriaceae, Clostridium, Lactobacillus, Vibrio, Pseudomonas and Photobacterium (Ababouch, 1991; Taylor, 1986; Lehane and Olley, 2000; Flick et al., 2001). Vibrio, Pseudomonas and Photobacterium species are indigenous bacteria found naturally in the marine environment and on fish whereas the mesophilic Enterobacteriaceae and C. perfringens typically occur as a result of post-harvest contamination. The enteric bacteria (especially Morganella morganii) tend to prevail during the summer season, whereas the indigenous bacteria may predominate during the winter (Okuzumi et al.,1984). The group of psychrophilic and halophilic bacteria named "N-group bacteria" were later identified as Photobacterium phosphoreum by Fujii et al. (1997).

Enterobacteriaceae species are the most important biogenic amines forming bacteria in fish. These include Morganella morganii, K. pneumoniae, Proteus vulgaris and Hafnia alvei (Frank, 1985). Since the most prolific histamine forming bacteria are mesophilic enteric bacteria, the formation of histamine, and probably of other biogenic amines, takes place at high rates at high temperatures (> 15 - 20°C) (Ababouch, 1991; Lehane and Olley, 2000; Flick et al., 2001). However, several other studies have also demonstrated that histamine and other biogenic amines can accumulate in fish to reach toxic levels even at low temperatures (Ababouch et al., 1991; Flick et al., 2001). Thus Jørgensen et al. (2000, 2000a) demonstrated that several biogenic amines were formed in vacuum-packed cold-smoked salmon stored at 5°C. Psychrotrophic lactic acid bacteria, Enterobacteriaceae and, especially, P. phosphoreum were the producing organisms. Whilst biogenic amines clearly may be formed in some fish at low temperatures, this is not common (Lehane and Olley, 2000; Flick et al., 2001) indicating that several factors, other than time and temperature play a major role.

Klausen and Huss (1987) reported that large amounts of histamine were formed by M. morganii at low temperatures (0 - 5°C) following storage at higher temperatures (10-25°C) even though bacterial growth did not take place at 5°C or below. It was argued that the enzyme histidine decarboxylase generated during storage at high temperature was responsible for subsequent histamine production at 5°C or below. Similar findings were reported by van Spreekens (1986). Biogenic amines are very heat stable and once formed, they will not be destroyed even by dramatic heat treatment such as autoclaving (Figure 5.6).

d) prevention and control

Histamine poisoning following the consumption of fish requires that:

Control of histamine poisoning can be achieved by eliminating one or more of these steps. It is worthy to recall that histamine is thermostable and once it is in the fish, there is no treatment capable of removing it. The most used methods for the control of histamine and biogenic amines formation in the fish industry are (FDA, 2001a):

Figure 5.6
Effect of heating on mackerel spiked with biogenic amines before autoclaving (Luten et al., 1992).

1) Rapid chilling of fish immediately after death. This is particularly important for fish that are exposed to warmer waters or air, and for large tuna that generate heat in the tissues of the fish following death. It is recommended that:

This will prevent the rapid formation of the decarboxylase enzymes. Once histidine decarboxylase is formed, control of the hazard is unlikely. Further chilling towards the freezing point is also desirable to safe-guard against longer-term, low temperature development of histamine. Additionally, the shelf-life of the fish is significantly compromised when product temperature is not rapidly dropped to near freezing.

2) Good hygienic practices on-board, at landing and during processing to avoid contamination or recontamination of the fish by bacteria capable of amino acid decarboxylation.

Freezing of the fish can significantly reduce the bacterial load, but will not limit the activity of decarboxylase enzymes that may have been produced prior to freezing. Therefore, it is important to know the temperature history of the frozen fish since outbreaks of histamine poisoning can be caused by the ingestion of thawed- frozen fish containing biogenic amines if the fish was previously temperature-abused (Flick et al., 2001).

Conflicting results have been reported on the effect of salting on biogenic accumulation (Flick et al., 2001). This reflects the diversity of the bacteria that are involved and their adaptation to different levels of salts. Likewise, bacteria producing biogenic amines are not equally affected by smoking and vacuum packaging and these procedures cannot therefore be relied upon to control biogenic amine accumulation. They have to be combined with refrigeration and limits on storage time to be efficient.

Because of the recurrence of histamine poisoning in many parts of the world and the importance of international trade of the concerned fish species, many countries have enacted maximal limits or guidelines on histamine levels in traded fish. Thus, the US Food and Drug Administration guidelines has established for tuna, mahi-mahi and related fish specify 50 mg/100 g (500 ppm) as the toxicity level, and 5 mg/100g (50 ppm) as the defect action level because histamine is not uniformly distributed in a decomposed fish. Therefore, if 5 mg/100g found in one section, there is a possibility that other units may exceed 50 mg/100g (FDA, 2001a). FDA requires the use of the AOAC fluorometric method (Rogers and Staruszkiewicz, 1997).

The European Union (EC 1991a, 1995) requires that nine samples must be taken from each batch of fish species of the following families: Scombridae, Clupeidae, Engraulidae and Coryphaenidae. These samples must fulfil the following requirements

However, fish belonging to these families which have undergone enzyme ripening treatment in brine may have higher histamine levels but not more than twice the above values, i.e. in preserved anchovies, it can be as high 200 and 400 ppm instead of 100 and 200 ppm. Examinations must be carried out in accordance with reliable, scientifically recognized methods, such as high-performance liquid chromatography (HPLC) (EC 1991a, 1995).

In Australia and New Zealand, the level of histamine in a composite sample of fish or fish products, other than crustaceans and molluscs must not exceed 10 mg/100g (100 ppm). A 'composite sample' is a sample, taken from each lot, consisting of five portions of equal size taken from five representative samples. This clause, which came into force in October 1994, is currently under review, with a proposal to increase the maximum allowable level of histamine in fish and fish products to 20 mg/100g (200 ppm) (Lehane and Olley, 2000).

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