Histamine Food Poisoning Toxicology and Clinical A

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Histamine Food Poisoning: Toxicology and Clinical Aspects
Article in Critical Reviews in Toxicology · February 1986

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Volume 17, Issue 2 91
HISTAMINE FOOD POISONING:

TOXICOLOGY AND CLINICAL ASPECTS
Author: Steve L. Taylor

Food Research Institute
University of Wisconsin
Madison, Wisconsin
Referee: Ronald R. Eitenmiller

Department of Food Science
Critical Reviews in Toxicology Downloaded from informahealthcare.com by Texas A&M Univ on 04/12/12
University of Georgia
Athens, Georgia
I. INTRODUCTION
Histamine, 4-(2-aminoethyl)imidazole (Figure l), is a primary amine arising from

the decarboxylation of the amino acid, L-histidine. The pKa of the amino group on the
side chain is 9 . 4 , while the pKa of the acidic imidazole nitrogen moiety is 5 . 8 . ' , * At a
physiological p H of 7.4, histamine occurs in the ionized state with side chain protona-
tion of about 3 % . Histamine may exist in a variety of different forms at physiological
p H considering its various states of ionization, the tautomeric properties, and the var-
For personal use only.
ious conformations of the side chain.* A slight change in pH from p H 6 to pH 7 can

change histamine from a charge acceptor to a charge donor.' It is not surprising that a
substance with such electronic properties is of major physiologic importance. In fact,
endogenous histamine plays important roles in a number of normal and abnormal
biological processes including vasodilation, anaphylaxis, and gastric acid secretion.'
Histamine also occurs exogenously in the food supply. Normally, the presence of
histamine in the diet has little consequence, since humans do not absorb histamine
efficiently from the gastrointestinal tract. However, on occasion, food-borne hista-
mine does cross the intestinal barrier. When this happens, histamine intoxication can
occur if sufficient quantities of histamine enter the bloodstream.
This review of histamine poisoning will primarily cover the clinical and toxicological
aspects of this food-borne illness. Information of the generation of histamine in foods
and its prevention will also be included. While some information will be provided on
the physiological effects of histamine, this review is not intended to provide complete
coverage of that complex subject.
11. CLINICAL ASPECTS
A. Definition
Histamine poisoning is a food-borne chemical intoxication resulting from the inges-
tion of foods that contain unusually high levels of histamine. The illness is an intoxi-
cation, so the incubation period is rather short ranging from several minutes to a few
hours following ingestion of the meal. The duration of the illness is typically short,
with symptoms subsiding within a few hours in most cases. In a few cases, symptoms
have persisted for several day^.^,'^ A case definition should include the rapid onset
time, the typical symptomology (detailed below), and the ingestion of the implicated
food.
Histamine poisoning has historically been referred to as scombroid fish poisoning
because of the frequent association of the illness with consumption of spoiled scom-
broid fish - such as tuna and mackerel. However, scombroid fish poisoning may be a
92 CRC Critical Reviews in Toxicology
CH2CHNH2 CH2CH2NH2
1
Histidine
7
decarbo x y lase
FIGURE 1. Formation of histamine by decarboxylation of L-histidine.
Table 1
SYMPTOMS OF HISTAMINE
POISONING
Cutaneous Hemodynamic
Rash Hypotension
Urticaria Neurological
Edema Headache
Localized inflammation Palpitations
Gastrointestinal Flushing
Nausea Tingling
Vomiting Burning
Diarrhea Itching
Cramping
misnomer, since nonscombroid fish and cheese have been involved in outbreaks of this
illness. Histamine poisoning is the preferred term which will be used throughout this
review. The Centers for Disease Control (CDC) and other public health agencies con-
tinue to refer t o the illness as scombroid fish poisoning and the causative agent as
scombrotoxin. The CDC lists cheese-related outbreaks under histamine as the causative
agent.
B. Symptomology
Histamine poisoning is usually a rather mild illness with a wide variety of possible
symptoms of cutaneous, gastrointestinal, hemodynamic, and neurological nature (Ta-
ble 1). In a review of 26 histamine poisoning incidents in Britain, Murray et al." list a
bright-red skin rash, flushing and sweating, and an oral burning or blistering sensation
(sometimes likened to a peppery taste) as the most common symptoms. Other symp-
toms noted less frequently were nausea, vomiting, diarrhea, stomach pain, headache,
swelling of the tongue, facial swelling, and dizziness. In a large U.S. outbreak, nausea,
abdominal cramps, the oral burning sensation, and diarrhea occurred in over half of
the cases.'* Facial flushing, headache, rash with occasional urticaria, vomiting, and
palpitations were also noted in this outbreak. Gilbert et al.I3 in a review of 30 outbreaks
involving I50 individuals noted diarrhea as the most commonly encountered symptom
with flushing and sweating, a bright-red rash, nausea, and headache as other frequent
symptoms. A number of other symptoms were encountered less frequently including
stomach pain, palpitations, the oral burning sensation, vomiting, a feverish sensation,
dizziness, tight chest, respiratory distress, and facial swelling. Kim'4 noted the frequent
occurrence of facial flushing in cases of histamine poisoning. Histamine is a potent
vasodilator, and hypotension can occur in some instances.lS More serious complica-
tions, such as cardiac manifestation^,'^.^' are rarely encountered in cases of histamine
poisoning.
The range of symptoms noted in particular outbreaks can vary somewhat as noted
above. The symptoms are often rather mild and usually of short duration, so the ac-
curacy of patient recall of the experience can be an important phenomenon. The list of
symptoms may depend to some extent on the nature of the questions being asked by
the interviewer.
Most patients suffering from histamine poisoning will experience only a few of the
symptoms noted above. Even in group outbreaks, it may not be possible to observe all
of these symptoms. The severity of the symptoms will also vary considerably in part
upon the amount of histamine consumed and the individual sensitivity of the patient
to ingested histamine.
C. Diagnosis
The diagnosis of histamine poisoning is usually based largely on a history of the
foods eaten by the patient immediately before onset of the illness. If the symptoms are
appropriate, the onset time is reasonably short, and the patient has eaten a type of fish
or other food that has previously been implicated in cases of histamine poisoning, then
a tentative diagnosis of histamine poisoning can be made. The diagnosis can be con-
firmed by detecting high levels of histamine in the implicated food, meal remnants or
a similar product obtained from the same source. Theoretically, vomitus could proba-
bly be analyzed for histamine to confirm the diagnosis, but this technique has never
been used to this author’s knowledge.
The symptoms of histamine poisoning are not definitive. Many of the symptoms can
occur with other illnesses, both food-borne and nonfood-borne. In patients who de-
velop only the gastrointestinal complaints, the diagnosis is particularly difficult be-
cause many other possible causes must be considered. The physician must be prepared
t o uncover the subjective complaints (the oral burning sensation, tingling, palpitations,
headache) that often accompany this illness. These symptoms may not be evident so it
is necessary to ask the appropriate questions. Objective measurements, such as blood
pressure monitoring, can be quite useful but must be conducted during the active phase
of the illness. The efficacy of antihistamines in the treatment of the symptoms also
provides important clues in the diagnosis of histamine poisoning.
Histamine poisoning is most often confused diagnostically with food allergies. Iden-
tical symptoms occur in food allergies and histamine poisoning, and antihistamines are
equally effective in treating both illnesses. Histamine poisoning can be easily distin-
guished from food allergy on the basis of (1) the lack of a previous history of allergic
reactions to the incriminated food, (2) the high attack rate in group outbreaks, and (3)
the detection of high levels of histamine in the incriminated food. Allergic reactions to
some of the foods commonly incriminated in histamine poisoning outbreaks, such as
tuna and mahi-mahi, are quite rare. With tuna, mahi-mahi, and many of the other
foods implicated in histamine poisoning incidents, histamine poisoning would be en-
countered much more frequently than allergic reactions. IgE-mediated allergic reac-
tions could be detected using skin prick tests with extracts of the incriminated foods.
Care must be taken to assure that the extracts used in the skin prick tests are prepared
from foods with low histamine contents since the presence of histamine in the extract
could give a false positive result. A negative skin test would point even more strongly
in the direction of histamine poisoning as the proper diagnosis. In group outbreaks,
the attack rate often, but not always, approaches 100%. When an outbreak involves
raw fish, the attack rate is sometimes substantially below loo%, because histamine is
not uniformly distributed in fish tissue^.^ Histamine in raw fish is usually present at
higher levels in tissue adjacent to the gills or the intestines, the main reservoirs of the
histamine-producing bacteria. With food allergies, it would be unusual for more than
one person in a group to experience symptoms to a specific food.
If certain foods, such as tuna and mahi-mahi, are eaten immediately before onset of
the illness, the likelihood of histamine poisoning is quite high. Only a few foods have
been implicated in the majority of outbreaks of histamine poisoning, so implication of
these foods raises suspicions. If the fish was consumed ra.w, the opportunities for tem-
perature abuse and histamine formation are enhanced, so that type of history is partic-
ularly suspicious. Confirmation of histamine as the cause of a food poisoning outbreak
can only be obtained by analysis of the implicated food.
D. Treatment and Avoidance

Antihistamine therapy is the optimal mode of therapy for histamine poisoning."
Symptoms usually subside rapidly after such treatment. H, antagonists, such as di-
phenhydramine or chlorpheniramine, are usually selected for the treatment of hista-
mine poisoning, although H2antagonists such as cimetidine may also be effective."
Since the disease is self-limited, pharmacological intervention may not be necessary in

mild cases.
Avoidance of certain types of fish and cheeses would be an effective means of pre-
vention of histamine poisoning, but such a drastic step is unnecessary given the spo-
radic occurrence of histamine poisoning. The avoidance of raw fish may be a more
reasonable approach. Many outbreaks in recent years have been associated with inges-
tion of raw fish. Elimination of raw fish from the diet would substantially reduce the
risk of histamine intoxication. Obviously, some individuals would choose to take this
risk, but they should be aware of this and other hazards associated with ingestion of
raw fish.
111. EPIDEMIOLOGY
A . World-Wide Occurrence
Histamine poisoning occurs world-wide, particularly in countries with substantial
consumption of certain types of fish. Illnesses with symptoms similar to histamine
poisoning were noted following consumption of fish as early as the ~ ~ O O S Only . ~ ~ ~ ~ '
sporadic incidents of histamine poisoning were recorded in the first half of this century
probably because histamine poisoning was a n unrecognized illness. Japanese scientists
were the first t o recognize histamine poisoning, and records of histamine poisoning
incidents in Japan are available from the early 1950s. More widespread recognition of
histamine poisoning in other countries did not begin to occur until about 1970. Since
1970, the countries with the most reported incidents of histamine poisoning are Japan,
the U.S., and Great Britain,22although this likely represents better reporting in these
countries to some extent. Less frequent incidents have been reported in various other
countries including Canada, New Zealand, France, Federal Republic of Germany, Ger-
man Democratic Republic, Norway, Sweden, Czechoslovakia, Netherlands, Australia,
Sri Lanka, Indonesia, South Africa, and Egypt.22Only a few of these countries keep
official records on incidents of histamine poisoning. It would be safe to assume that
many incidents in these and other countries are not reported.
1 . Japan
Histamine poisoning was recognized as a major cause of food-borne disease in Japan
in the early 1950s. Kawabata et aLZ3published epidemiological information on 14 in-
cidents of histamine poisoning that occurred in Japan from October 195I through
October 1954. These incidents involved a total of 1215 cases. The first of the incidents
involved 700 individuals, which remains one of the largest outbreaks on record. A total
of 11 of these 14 incidents were associated with the ingestion of samma sakuraboshi, a
dried seasoned saury ( Cololabis saira). Iwashi sakuraboshi, canned mackerel (Scomber
japonicus), and frigate tuna (Auxis thazard) were implicated in the remaining three
incidents.
Histamine poisoning remains a major food-borne disease in Japan. A summary of
Table 2
HISTAMINE POISONING IN JAPAN (1970-1980)
No. of No. of
Year outbreaks cases Implicated food (no. of outbreaks)
1970 5 178 Mackerel (2)

Horse mackerel (1)
Tuna (1)
Unknown (1)
1971 2 70 Tuna (1)
Mackerel ( 1 )
1972 4 137 Tuna (2)
Mackerel (1)
Chicken (1)
1973 3 2702 Horse mackerel (2)
Anchovies (1)
1974 1 33 Kamaboko (1)
1975 7 396 Tuna (3)
Mackerel (1)
Spanish mackerel (1)
Sardines (1)
Scombroid fish ( 1 )
1976 4 31 Tuna (2)
Mackerel (1)
Scombroid fish ( I )
1977 3 69 Tuna (1)
Sardines (1)
Black marlin ( 1 )
1978 2 32 Tuna ( 1 )
Mackerel (1)
1979 7 321 Tuna (5)
Striped marlin (1)
Dorado ( 1 )
1980 4 153 Tuna (2)
Mackerel (1)
Sardines (1)
From data compiled by Ministry of Health and Welfare, Japan.”
histamine poisoning outbreaks in Japan for the period of 1970 to 1980 is provided in
Table 2. A much wider variety of fish were implicated in the recent incidents by com-
parison to the situation in 1951 to 1954. Given the Japanese preference for raw fish, it
is somewhat surprising that cooked fish were involved in more histamine poisoning
incidents than raw fish. The utilization of only the highest quality fish in the raw fish
market in Japan is probably responsible for this observation. Most of the incidents
involved a large number of cases; only 13 of the 42 outbreaks involved fewer than 10
individuals, while 9 incidents involved more than 50 people. The largest outbreak oc-
curred in 1973 and involved 2656 people. This incident resulting from the consumption
of dried horse mackerel (Trachurusjaponicus) is the largest recorded outbreak of his-
tamine poisoning world-wide. Large outbreaks are much more likely to be reported to
the health authorities than small-scale outbreaks. This tendency is probably responsible
for the preponderance of large outbreaks in the Japanese health records.22 It may also
indicate that smaller outbreaks are not being reported in Japan leading to a consider-
able underestimation of the total number of outbreaks. The awareness of histamine
poisoning in Japan has been enhanced by the publication of several incidents in Japa-
nese l i t e r a t ~ r e . ’2~9
Table 3
HISTAMINE POISONING IN THE U.S.
(1968- 1981)
No. of No. of Implicated food

Year outbreaks cases (no. of outbreaks)
1968 3 19 Tuna (2)

Mahi-mahi (1)
1969 1 3 Mackerel (1)
1970 1 2 Bonito (1)
1972 6 ? Mahi-mahi (2)
Tuna (1)
Albacore (1)
Pork fish (1)
Marine fish (1)
1973 I2 326 Mahi-mahi (6)
Tuna ( 5 )
Ulua or jack (1)
1974 10 26 Tuna (6)
Mahi-mahi (1)
Spanish mackerel (1)
Red snapper (1)
Kumu-red goat fish (1)
1975 6 16 Tuna (3)
Mahi-mahi (2)
Skipjack (1)
1976 3 43 Tuna (1)
Mahi-mahi( 1)
Swiss cheese (1)
1977 13 71 Tuna (5)
Mahi-mahi (3)
Bluefish (3)
Yellow tail (1)
Anchovies (1)
1978 7 30 Mahi-mahi (7)
1979 12 132 Mahi-mahi (5)
Tuna (2)
Other fish (5)
1980 29 153 Mahi-mahi (21)
Tuna (3)
Other fish (5)
1981 7 67 Tuna (4)
Mahi-mahi (2)
Other fish (1)
Compiled from Centers for Disease Control, Annual Sum-

maries o f Foodborne and Waterborne Disease Out-
breaks, Atlanta.
2. U.S.
The CDC initiated its food-borne disease surveillance program in 1966. Before that
time, no system existed in the U.S. for the collection and compilation of data relating
t o histamine poisoning or other types of food-borne disease. The first episodes of
histamine poisoning reported through the surveillance program occurred in 1968. As
shown in Table 3, a total of 110 outbreaks of histamine poisoning were reported in the
U.S. from 1968 through 1981. Histamine poisoning is one of the most prevalent forms
of food-borne disease of chemical etiology in the U.S., ranking only behind ciguatera
poisoning.30 In contrast t o the Japanese situation, most of the U.S. outbreaks involve
a small number of people, typically less than five individuals. A large outbreak of
histamine poisoning occurred in 1973 involving commercially canned tuna. 13.31,32This

outbreak remains the largest on record in the U.S. and signaled an increasing aware-
ness of histamine poisoning in that country. Accounts of some of the other histamine
poisoning outbreaks have also been p ~ b l i s h e d . ~ , ' 46~ ,The
' ~ . ~continued
~ reporting of
sporadic incidents of histamine poisoning is probably important to enhance the aware-
ness of this illness among physicians and increase the likelihood that they will report
future episodes. The 110 reported incidents in the U.S. probably represent only a frac-
tion of the total number of outbreaks that occurred from 1966 to 1981. Although CDC
compilations for 1982 to 1985 are not yet available, evidence indicates that outbreaks
of histamine poisoning continue to occur. 1 9 . 4 2 4 5
3. Great Britain
Perhaps the earliest account of histamine poisoning occurred among a group of
British sailors aboard the Triton of Leith in 1828.21Five crew members became ill with
symptoms of severe headache, dilated blood vessels, edema, facial swelling and flush-
ing, swelling of the entire body, and shivering following the consumption of bonito.
Bonito is a scombroid fish and a likely vehicle for histamine poisoning. The symptoms
are also consistent with a diagnosis of histamine poisoning.
After this early incident, reports of histamine poisoning in Great Britain virtually
disappeared until 1976. From 1976 to the present, over 100 episodes of histamine poi-
soning have been reported in England, Wales, and Scotland (Table 4)-11.13.22,47 49 The
sudden increase in reports of histamine poisoning in Great Britain appears to be related

to an increase in the consumption of mackerel and a concomitant decrease in the con-

sumption of herring.48 Mackerel, especially smoked mackerel, accounted for the vast
majority of the outbreaks from 1976 to 1980 and continued as a common culprit
through 1982. The decrease in the numbers of outbreaks related to mackerel in 1981
and 1982 has been attributed to improved handling and storage practices, particularly
low storage t e m p e r a t ~ r e s With
. ~ ~ the increased awareness of histamine poisoning re-
sulting from the mackerel incidents, reports of histamine poisoning in Great Britain
began t o incriminate other types of fish. Presently, tuna, sardines, herring, and pil-
chards as well as mackerel are commonly implicated in histamine poisoning episodes
in Great Britain. Reporting of histamine poisoning may be much more complete in
Great Britain than other countries because it is one of the few countries where hista-
mine poisoning is a notifiable illness.
4. Other Countries
Reports of histamine poisoning from other countries are rather sporadic. Some of
these countries lack adequate systems for reporting and investigating outbreaks of
food-borne disease. Histamine poisoning seems likely to occur in any country where
fish is consumed. However, the type of fish consumed and the method of harvesting
are important factors in determining the likelihood of histamine poisoning. The situa-
tion in Great Britain shows clearly that the frequency of histamine-poisoning episodes
may change dramatically as consumption patterns are Finland, Norway,
Sweden, and Iceland report few histamine poisoning outbreaks despite a high level of
consumption of fish. The fish eaten most often in these countries are not susceptible
t o histamine formation and catching and storage temperatures are low, which mini-
mizes histamine formation. In a few countries, the low frequency of histamine poison-
ing episodes is difficult to explain. In Canada, a good disease surveillance program
exists, and tuna and mackerel are frequently consumed; yet, Canada has reported only
a few outbreaks of histamine poisoning. The widespread occurrence of histamine poi-
soning will be obvious from a review of the published reports of the illness.
Legroux et 53 in France reported some of the earliest episodes of histamine
Table 4
HISTAMINE POISONING IN BRITAIN
(1976-1982)
No. of No. of Implicated food

Year outbreaks cases (no. of outbreaks)
1976 3 9 Smoked mackerel (3)

Canned mackerel (2)

Mackerel paste (1)
Bonito (1)
Sprats (1)
Canned pilchards (1)
Canned sardines (1)
Canned mackerel (1)
Mackerel paste (1)
Soused mackerel (1)
Canned tuna/bonito (10)
Canned sardines (5)
Raw tuna (1)

Canned mackerel (1)
Brined mackerel (1)
Canned tuna (9)
Canned sardines (3)
Canned anchovies (1)
Canned kipper fillets (1)
Frozen mackerel (1)
Raw mackerel (1)
Canned tuna (10)
Canned sardines (2)
Herring, pickled or kippered (4)
Gefilte fish (1)
From Taylor, S. L., Histamine Poisoning Associated with Fish,

Cheese, and Other Foods, Monograph, World Health Organiza-
tion, Geneva, 1985.’*
poisoning. Their investigations provided some of the earliest evidence that histamine
was the causative agent in such outbreaks. Fresh albacore (Thunnus alalunga) was
implicated in these early French outbreaks from the 1940s. In 1956, a large outbreak
of histamine poisoning occurred in France involving almost 500 people.s4 That incident
and a smaller outbreak in 196355involved “fresh” tuna ( T . fhynnus). From 1980 t o
1983, 10 additional episodes of histamine poisoning have occurred in France.” Tuna
was implicated in five of these incidents with the others attributed to sardines, herring,
ham, and Gruyere cheese.
Published accounts of several outbreaks of histamine poisoning from the Federal
Republic of Germany and the German Democratic Republic have a p p e a ~ e d . Two ~~.~~
incidents involving mackerel occurred in the German Democratic Republic,” while
outbreaks implicating sardines, tuna, smoked mackerel, and possibly sauerkraut were
reported from the Federal Republic of Germany.58 6 3
Denmark has kept statistics on histamine poisoning since 1976. A total of 33 inci-
dents occurred from 1976 through 1982.22 Most of the episodes involved only a few
people, although one large outbreak did occur in 1982. All of these incidents involved
either tuna or mackerel. A published report arose from one of these
Isolated episodes of histamine poisoning have been reported from other European
countries including one outbreak from tuna in another incident implicating
tuna in C z e c h o ~ l o v a k i a two , ~ ~ episodes from the Netherlands involving Gouda cheese
in one case67 and fish in the other case,68 and one incident from Sweden implicating
tuna.69 From published accounts of research on the control of histamine formation
and reviews of histamine p o i ~ o n i n g , it~ could ~ - ~ ~ probably be assumed that histamine
poisoning is also a problem in Italy, Poland, Hungary, and Turkey. However, pub-
lished accounts of outbreaks from those and other European countries are not in evi-
dence, and statistics on histamine poisoning are not kept.
Canada has experienced six episodes of histamine poisoning from 1975 to
198 J - 1 0 . 7 4 - 7 5 All of the incidents involved five or fewer individuals. Fish - tuna, mahi-
mahi, and smoked mackerel - were implicated in five of the six episodes, while the
other incident was attributed t o cheddar cheese.
Several incidents of histamine poisoning were reported from New Zealand and the
nearby British Solomon Islands in 1973 to 1975.77-81 These episodes involved no more
than ten people and implicated skipjack tuna, mackerel, kahawai, kingfish, and trum-
peter fish. Curiously, no further incidents have been reported from New Zealand.
Several unusual episodes of histamine poisoning have been reported from Sri
Lanka.17.82-85These incidents involved tuberculosis patients on isoniazid therapy, and

tuna were implicated in every case. These outbreaks illustrate the possible potentiation
of histamine poisoning by isoniazid. Two of these episodes were rather large, involving
21 and 56 patients, r e s p e ~ t i v e l y . ~ ~ ~ ~ ~
Single outbreaks of histamine poisoning have also been reported from Australia
(bluefish), South Africa (tuna), Bermuda (mahi-mahi),86 and Indonesia (tuna).87 The
South African outbreak was rather large, involving 7 0 patients in a hospital. Other
countries including Egypt, Republic of Korea, and People’s Republic of China proba-
bly experience occasional outbreaks of histamine poisoning.22 In all likelihood, the
occurrence of this food-borne disease is virtually world-wide.
B. Foods Implicated in Histamine Poisoning

1. Fish
Fish have been implicated in most of the outbreaks of histamine poisoning. The fish
most commonly involved in histamine poisoning are listed together with their scientific
names in Table 5 . The scientific names were taken from Bailey et a1.88and Wheeler.89
The so-called scombroid fish, which belong to the families Scomberesocidae and Scom-
bridae, have been most frequently implicated in histamine poisoning. The various spe-
cies of tuna, skipjack, bonito, albacore, mackerel, Spanish mackerel, bluefin tuna, and
saury are included in the scombroid fish category. Most of the scombroid fish have
been implicated in outbreaks of histamine poisoning. Tuna, mackerel, and skipjack
are most frequently involved, but this is partially due t o the greater consumption of
these fish world-wide. Some of the other scombroid fish are less commonly consumed
and consequently are only infrequently implicated in outbreaks. However, certain
scombroid fish may have less susceptibility to histamine formation. Albacore, for ex-
ample, has been implicated in only a few episodes of histamine poisoning despite con-
siderable consumption of this fish. The involvement of all of the scombroid species
listed in Table 5 cannot be documented. In many cases, the exact species of tuna o r
mackerel implicated in an outbreak is not specified. However, based on the docu-
mented incidents and the close relationships between the species, it is assumed that
Table 5
FISH SPECIES THAT MAY BE IMPLICATED IN HISTAMINE POISONING
Scientific name
Common name Family Genus and species
Scombridae
Yellowfin tuna Thunnus albacares
Blackfin tuna T. atlanticus
Southern bluefin tuna T. maccoyiior T. thynnus maccoyii
Big-eye tuna T. obesus or Parathunnus mebachi

Atlantic bluefin tuna T. thynnus thynnus
Pacific bluefin tuna T. thynnus orientalis
Longtail tuna T. tonggol
Albacore T. alalunga
Skipjack tuna Euthynnus pelamis or Katsuwonas pelamis
Kawakawa E. affinis
Little tunny E. alletteratus
Black skipjack E. lineatus
Slender tuna Allothunnus fallai
Bullet tuna or bullet mackerel A uxis rochei
Frigate tuna, frigate mackerel, or A. thazard
plain bonito
Atlantic bonito Sarda sarda
Indo-Pacific or striped bonito S. orientalis

Eastern Pacific bonito S. chiliensis
Australian bonito S. australis
Atlantic mackerel Scornber scombrus
Chub or Pacific mackerel S. japonicus
King mackerel Scomberomorus cavalla
Spanish mackerel S. maculatus
Monterey Spanish mackerel S. concolor
Cero S. regalis
Sierra S. sierra
Scomberesocidae
Atlantic saury Scomberesox saurus
Pacific saury or mackerel pike Cololabis saira
Pomatomidae
Bluefish Pomatomus saltatrix
Coryphaenidae
Dolphin fish, dorado, or mahi-mahi Coryphaena hippurus
Carangidae
Horse mackerel Trachurus trachurus or T. japonicus
Jack mackerel T. symmetricus
Pacific amberjack Seriola colburni
Yellowtail S. dorsalis or S. grandis
Greater amberjack S. dumerili
Clupeidae
Atlantic herring Clupea harengus harengus
Pacific herring C. harengus pallasi
Sprat or brisling C. sprattus
Pacific sardine or pilchard Sardinops sagax
Pilchard or sardine Sardina pilchardus
Golden sardine Sardinella aurita
Spanish sardine S. anchovia
Engraulidae
European anchovy Engraulis encrasicolus
Pacific or northern anchovy E. mordax
Anchoveta Centengraulis mysticetus
other species may be involved. To clarify this situation, it would be desirable to identify
the species involved by its scientific name in outbreaks whenever possible.
Certain types of nonscombroid fish can also be involved in outbreaks of histamine
poisoning. All of the implicated species are marine fish. Some variations exist in the
types of nonscombroid fish involved in outbreaks in different countries. In the U.S.,
mahi-mahi ( Coryphaena hippurus) is the most commonly implicated nonscombroid
fish in incidents of histamine poisoning (Table 3). In fact, mahi-mahi has become a
major source of histamine poisoning in the U.S., paralleling an increase in the availa-
bility of that fish. Only scattered reports of histamine poisoning from mahi-mahi have
appeared from other countries. Single episodes have occurred in Canada, 74 Bermuda,86
and Japan (Table 2, the name for mahi-mahi in Japan is dorado). Mahi-mahi may be
less popular in other countries by comparison to the U.S.
Sardines have been implicated in episodes of histamine poisoning in the Federal
Republic of Germany,58 Great Britain (Table 4), and Japan (Table 2). Although sar-
dines are commonly consumed in the U.S. and the Scandinavian countries, histamine
poisoning following sardine ingestion has not been reported in those countries. The
involvement of sardines has been relatively recent and may parallel the increased export
of sardines from warm locales. Britain has also experienced outbreaks associated with
pilchards and herring (Table 4), species related to sardines. Their first incident involv-
ing pilchards was not identified until March 1982, but nine incidents involving pil-
chards were recorded in 1982 making it a major cause of histamine poisoning in Great
Britain.22Pilchards have not been implicated in histamine poisoning in other countries,
although pilchards may not be differentiated from sardines in some markets. Herring
have been implicated in five histamine poisoning episodes in Great Britain since 1981
(Table 4). Again, other countries have failed to report any incidents involving herring.
Sugar-salted, fermented herring frequently contain high levels of histamine, but these
fish have not been implicated as causing illness.22
Bluefish, Pomatomus saltatrix, are another nonscombroid species that have been
implicated in episodes of histamine poisoning. Several bluefish-related outbreaks have
occurred in the U.S. (Table 3),44 and one episode has occurred in Australia.22
The Carangidae family, another nonscombroid group, can also be involved in his-
tamine poisoning. The jack mackerel ( Trachurus symmetricus) is probably responsible
for some of the mackerel-related outbreaks. The horse mackerel (T. trachurus) has
been implicated in several incidents in Japan (Table 2).
Other nonscombroid fish have been involved in isolated episodes of histamine poi-
soning. Anchovies have been implicated in single episodes in the U.S. (Table 3) and
Japan (Table 2). Kahawai was involved in an episode in New Zealand.7’ Likewise,
trumpeter fish were implicated in a possible histamine poisoning episode in that coun-
try.*’ Black marlin and striped marlin were each implicated in single episodes in Japan
(Table 2).,,
Misidentification of the fish involved in outbreaks of histamine poisoning may occur
on occasion especially in single cases or episodes where the patient’s identification of
the fish must be relied upon. Some confusion also exists based on the different com-
mon names used for the same species of fish in different countries. The use of the
scientific names for the fish only partly resolves this problem, because the scientific
terminology is not necessarily settled for all of the involved marine species.
2. Cheese
Recently, the potential role of cheese in outbreaks of histamine poisoning has been
realized. The first account of cheese associated with histamine poisoning occurred in
the Netherlands and involved a person who became ill after eating Gouda cheese that
had been aged for a n unusually long period of time.67 Because of the unusual aging,
the significance of this incident was underestimated by many scientists. However, in

1978, a major outbreak of histamine poisoning occurred in the U.S. involving 38 cases
and incriminating Swiss A second and smaller Swiss cheese-related outbreak
also occurred in the U.S.; this episode involved only six individual^.^' One episode of
histamine poisoning implicating Gruyere cheese has been reported in France.22Several
cases of histamine poisoning have been described in patients on isoniazid t h e r a ~ y ; ~ ~ . ’ ’
one implicated cheddar while the other was associated with “Cheshire”
cheese.” Cheese can occasionally contain appreciable levels of h i ~ t a m i n e . ~ ~The
.~~.”
possible role of cheese in future cases of histamine poisoning should be recognized.
3. Other Foods
On four occasions, other foods have been implicated in incidents of histamine poi-
soning. Chicken was implicated in one incident in Japan (Table 2); sauerkraut was
possibly involved in an episode in the Federal Republic of Germany;63 shellfish was
implicated in a single U.S. incident (Table 3); and ham was involved in an outbreak in
France.22In each of these incidents, firm evidence linking these foods with histamine
poisoning was lacking. Further substantiation including additional confirmed episodes
will be needed t o establish any role for these foods in histamine poisoning.
Other foods not known to be implicated in outbreaks of histamine poisoning can
possess high levels of histamine on occasion. Proteinaceous foods subjected to putre-
faction and fermented foods are particularly likely to contain large amounts of hista-
mine. S a ~ e r k r a u t , ~~~i.n’ e~ , ’ ~ and
. ’ ~ fermented, dry sausage^^^^^^ such as Italian salami
and pepperoni are known to have high levels of histamine on occasion.
C. Constraints to Surveillance
Good statistics on the prevalence of histamine poisoning world-wide do not exist.
Many countries with high fish consumption and a resultant high likelihood for hista-
mine poisoning d o not keep any statistics on food-borne disease. Even in countries
with adequate reporting programs, the incidence of histamine poisoning is probably
much higher than reported. For several reasons, outbreaks and cases of histamine poi-
soning are often not reported. Histamine poisoning is a relatively mild illness of short
duration in most cases. Thus, many patients do not seek medical attention. Many
physicians remain unaware of histamine poisoning and do not consider it as a possible
diagnosis. Histamine poisoning can also be misdiagnosed rather easily as some other
type of food-borne disease or a food allergy. Even when medical attention is sought
and a correct diagnosis is made, histamine poisoning is not a notifiable illness in most
countries, and many cases are not reported to the public health authorities. Thus, the
true incidence of histamine poisoning is unknown.
IV. FORMATION OF HISTAMINE AND ITS CONTROL
A. Formation of Histamine
1. Histidine Decarboxylase (EC 4.1.1.22) Reaction
Histamine in foods arises from the amino acid, L-histidine, by an enzymatic decar-
boxylation reaction catalyzed by histidine decarboxylase (Figure 1). Early investigators
believed that histamine formation was an autolytic p r o c e ~ s . ~However,
*.~~ it is now
known that the bulk of the histamine formed in foods is the result of the growth of
bacteria that possess the enzyme, histidine decarboxylase. 99 Scombroid fish are com-
monly involved in histamine poisoning because they possess large amounts of free
histidine in their muscle This free histidine serves as a substrate for bac-
terial histidine decarboxylase. Proteolysis, either autolytic or bacterial, may play a role
in the release of free histidine from tissue proteins. Proteolysis may be especially im-
portant in the formation of histamine in cheese since milk does not contain large quan-
tities of free histidine.
2. Bacteria Possessing Histidine Decarboxylase

Histidine decarboxylase is not widely distributed among bacteria. The enzyme is
found in certain species of Enterobacteriaceae (especially Proteus species), Clostri-
dium, and Lactobacillus. Even among individual species within these groups, histidine
decarboxylase is rarely present. All of the strains of some species such as Proteus mor-
ganii seem to possess histidine decarboxylase, L02,103while the enzyme is present in only
a few strains of other species such as Klebsiella p n e u m ~ n i a eand ' ~ ~ Lactobacillus buch-
neri.lo5 Taylor et a1.'02 provide a list of bacteria that are known to possess histidine
decarboxylase. However, evidence firmly linking some of the bacterial species on that
list to histamine production is lacking. Many studies of bacterial histamine production
were not comparative, and it is therefore difficult to determine if histamine production
by these bacteria is prolific or inconsequential. In studies of bacterial histamine pro-
duction, a preferable procedure would be to compare the rate and extent of histamine
formation to known prolific histamine producers such as P . morganii. In many pre-
vious studies, histidine decarboxylase activity was measured directly, which ignores the
possible role of histaminase activity in some bacteria. Histaminase is not widely dis-
tributed among bacteria either, but it has been found in several The
measurement of histamine production is preferred over the measurement of histidine
decarboxylase activity. Two media have been widely used to identify histamine-pro-
ducing bacteria: tuna fish infusion broth (TFIB), a poorly defined medium prepared
from the muscle tissue of raw tuna,'OB and a histidine-fortified trypticase soy broth
(TSBH), a defined medium prepared to maximize bacterial histamine p r o d ~ c t i o n . ' ~ ~
These media are particularly useful in the identification of histamine-producing Entero-
bacteriaceae. A differential medium for the isolation of histamine-producing organ-
isms from fish has also received wide use. ' l o For the identification of histamine-pro-
ducing lactobacilli, a histidine-fortified MRSIIonbroth has been used.'05
Enteric bacteria are the most important histamine-producing bacteria in fish. P.
r n ~ r g a n i i , ~K~ .. pneumoniae,
~' Io4 and Hafnia alvei" ' are the only histamine-producing
bacteria that have actually been isolated from fish implicated in histamine poisoning
incidents. However, other histamine-producing enterics have been isolated from
spoiled fish. 102.108.113 Enterobacter aerogenes is the only other enteric species identified
thus far whose histamine-producing capabilities appear to be equivalent to P. rnorganii
or the histamine-producing strains of K . pneumoniae. Io2 Behling and Tay10r"~showed
that histamine-producing bacteria can be divided into two categories: those species
capable of producing large quantities of histamine (>I00mg/100 m i ) in TFIB within
24 hr at temperatures above 15°C and those species that produce lesser amounts of
histamine (<25 mg/100 m i ) in TFIB after more prolonged incubation (248 hr) at tem-
peratures of 30°C or higher. P . morganii, K . pneumoniae, and E . aerogenesbelong to
the category of prolific histamine producers, while the tested strains of H . alvei, Cifro-
bacter freundii, and Escherichia coli were slow producers of histamine. Similar re-
sults were obtained by Arnold et al.1'5 in a comparison of two prolific histamine pro-
ducers, P. morganiiand P . vulgaris, with a slow histamine producer, H . alvei. Most
of the previously identified histamine-producing bacteria from the listing provided by
Taylor et al.'O2 probably belong in the slow producer category. However, other bacte-
rial species and strains with prolific histamine-producing capabilities likely remain to
be identified. The recent isolation of Clostridium perfringens from decomposing skip-
jack tuna and its identification as a prolific histamine producer'I2 would seem to un-
derscore this point. The as yet unidentified N-group bacteria capable of histamine
production at low temperatures in the presence of salt may be another exam-
p1e~113,116.117
The enterics would Be predicted to have little importance in the production of his-
tamine in cheese. The organisms responsible for histamine production in cheese have
received little attention, and few have been identified. Salt-tolerant lactobacilli may
have been responsible for histamine formation in the Gouda cheese implicated in a
histamine poisoning episode in the Netherlands,'" but these organisms were never
identified or carefully evaluated for their abilities to produce histamine. Edwards and
Sandine1I9attempted to isolate histamine-producing bacteria from Swiss cheese with-
out much success. They identified some histamine-producing bacteria including Strep-
tococcus faecium, S. mitis, Lactobacillus bulgarius, L. plantarum, streptococci of the
viridans group, and propionibacteria, but these organisms did not appear to be prolific
histamine producer~."~ Recently, a strain of L. buchneri was isolated from a sample

of Swiss cheese implicated in an outbreak of histamine poisoning and shown to be a
prolific histamine This strain of L. buchneri appears to be unique, since
other tested strains of this species did not produce histamine. '04 Other histamine-pro-
ducing lactobacilli have been identified.119-'z'One of these strains, known as Lacto-
bacillus 30a, is able to produce large quantities of histamine.'z2 The histidine decarbox-
ylase of Lactobacillus 30a has been purified and extensively c h a r a c t e r i ~ e d . The
~~~~'~~
enzyme from L. buchneri has also been purified and seems to be quite similar to the
enzyme from Lactobacillus 30a. 124,125 Biochemical characterization of Lactobacillus
30a revealed that it most closely resembles L. delbrueckii.'22However, DNA from a
known strain of L. delbrueckii was only 29% homologous with DNA from Lactoba-
cillus 30a, so this may be a novel species.'zzThe ability to produce histamine appears
to be limited to only a few strains of lactobacilli. However, this ability is possessed by

widely divergent lactobacilli; Lactobacillus 30a is homofermentative while L. buchneri
is heterofermentative. Further research will be needed to determine if additional species
of dairy-related bacteria are capable of significant histamine production. However, it
is unlikely that commonly used starter cultures serve as sources of histamine.1z6~12' In
fact, some starter culture organisms possess amine oxidase activity.1ze
B. Control of Histamine Formation

1. Introduction
Several preventive measures can be taken to control histamine formation in foods.
The nature of the food product must be taken into consideration in the development
of such control measures. With fish, low temperature storage and good hygienic prac-
tices are crucial to the control of bacterial histamine formation. Yet, these practices
may be difficult to implement in certain locales. Also, these preventive measures may
not be effective for other products such as cheese.
2. Low Temperature Storage of Fish

In the fishing industry, low temperature storage after catching is the key to the con-
trol of bacterial histamine production. The histamine-producing bacteria apparently
reside in the gills and/or intestines of the f i ~ h . ~ . Any
' ' ~ extended storage of fish at
elevated temperatures results in bacterial invasion of the muscle tissues and conversion
of tissue histidine to histamine, if the bacteria are histamine producers. Many of the
fish species commonly implicated in outbreaks of histamine poisoning, such as tuna
and mahi-mahi, are often caught in warm water. If the fishing boat is a purse seiner,
the fish may remain in the nets at this elevated temperature for several hours after
catching. Once on board the fishing vessel, the fish may or may not be cooled and the
methods of cooling will vary widely in their efficiency. American purse seiners are
typically equipped with refrigeration units and cool the fish in holds filled with refrig-
erated seawater. Once the hold is full, the fish can be frozen. Baitboats usually rely on
ice for cooling. In other countries, cooling facilities may be less common on boats.
Volume 17. Issue 2 105
The rate of cooling will depend on the size of the catch. The fish are not eviscerated
until they reach the processing plant. The possibility of fish being held at elevated
temperatures for significant periods of time certainly exists. Variable conditions exist
from boat to boat, and this probably explains the sporadic occurrence of histamine
poisoning.
Incubation temperature has a profound effect on bacterial histamine formation in
media. Arnold et al.Il5 determined that histamine production by P . morganii and P .
vulgaris was optimal at 30°C and was substantially delayed and diminished by incu-
bation at 7°C. Similar results were obtained by Behling and Taylor"' with P . morganii
and K . pneumoniae. Only K . pneumoniae was able to generate significant amounts of
histamine at 7"C, and prolonged incubation was necessary even in that case.114 P.
morganii and P . vulgaris had lower temperature limits for histamine formation of 15
t o 19"C.114,115 For slow histamine producers such as H . alvei, C. freundii, and E . coli,
the lower temperature limit for histamine production was 30°C, and, even at such
elevated temperatures, prolonged incubation was required. 114.115 Most histamine-pro-
ducing bacteria are mesophilic, and low temperature storage effectively controls their
growth. However, the possible existence of psychrophilic, histamine-producing bacte-
ria cannot be discounted. Psychrophilic, histamine-producing bacteria have been iden-
tified occasionally: one report involved a C. freundiiisolate,26while the other involved
psychrophilic, halophilic N-group bacteria. 1 1 6 . 1 1 7 The exact identity of these N-group
bacteria has never been established.
Many studies have been performed on the effect of storage temperature on histamine
formation in various types of fish. All studies seem to agree that histamine formation
is negligible in fish stored a t 0°C or below.70~130-136 However, the results, both with
respect to optimal temperature and lower temperature limit for bacterial histamine
formation in fish, were variable. The optimal storage temperature for histamine for-
mation in fish was as low as 15 to 20°C in some ~ t ~ d i e and ~ ~as high
~ . as~ 30~t o~ . ~ ~ ~
38°C in a few s t ~ d i e s . ' ~In
' . ~the ~ ~majority of investigations, the optimal storage tem-
perature was 20 to 25°C.131,134.139 1 4 2 One study indicated little difference in the
amounts of histamine formed in fish as a function of storage temperature from 10 to
37"C.143Several studies have supported a lower temperature limit for histamine for-
mation in stored fish of about 10°C with little histamine formation occurring at storage
temperatures of 2 to 10"C.131 1 3 5 , 1 4 0 In contrast, other investigators found substantial
histamine formation in fish at storage temperatures of 0 to 10°C.70.130.132.136,142.144

Frank et al.145have developed a nomograph for estimating the rate of histamine for-
mation in skipjack tuna on storage at elevated temperatures. This nomograph accu-
rately reflects the results obtained in their earlier spoilage However, their
studies indicated that the optimal temperature for histamine formation was 37"C, and
this finding is not in agreement with many other studies as noted above. The nomo-
graph approach is commendable in principal and should be extended to other species
of fish and lower storage temperatures.
The variable results obtained in these studies on the formation of histamine in fish
as a function of storage temperature may be due to differences in the type and level of
bacterial flora in the fish used in the various studies. Histamine-producing bacterial
species and strains vary considerably in their optimal temperature and lower tempera-
ture limits for histamine formation as noted above. Also, there is no reason to believe
that all of the fish used in these storage studies possessed histamine-producing bacteria
or that the histamine producers were among the predominant microflora. The preva-
lence of histamine-producing bacteria in scombroid fish and other relevant types of
fish is unknown. The identity of the histamine-producing bacteria was established in
only three of the fish storage studies. Sakabe,'43 Ganowiak et al.,71and Fernandez-
Salguero and M a ~ k i e inoculated
'~~ some of the fish in their studies with P . rnorganii
before storage. Certainly, the level of histamine-producing bacteria would also affect
the rate of histamine formation in a storage study.
Current fishing practices which involve either immediate icing or storage in refrig-
erated seawater at approximately -1 "C with later freezing should control bacterial
histamine formation. The production of relatively large quantities of histamine in sev-
eral studies at 4 to 6°C70.130may be an additional indication that psychrophilic hista-
mine-producing bacteria exist. However, a n alternative explanation is possible. Fish
subjected to a short period of storage (1 day) at 20°C will yield high levels of histamine
following subsequent storage at refrigeration temperatures. 1 4 3 Alternatively, histamine
is generated slowly in fish stored at -8°C prior to subsequent storage a t 29°C.'' Pre-
sumably, freezing injures the histamine-producing bacteria, which limits their prolif-
eration and histamine-producing capabilities. However, with careful control of storage
temperatures, rapid cooling of catches, and limitations on the length of storage in
refrigerated seawater before freezing, histamine formation should be minimized.
Other methods may also be useful for the control of histamine formation during fish
storage. Watts and determined that storage of mackerel at 20°C in an 80%
CO, atmosphere was preferable to ambient air storage. Histamine formation and gen-
eral spoilage were retarded by storage in the modified atmosphere, although the differ-
ences disappeared by the third day of storage at 20°C. The effect of modified atmos-
phere storage needs to be evaluated at lower temperature. However, this type of
alternative storage will not likely be easily implemented on fishing vessels and will
likely be reserved for storage of fresh and frozen fish in transit from port to market.
3 . Hygienic Practices to Avoid Contamination

Histamine-producing bacteria have been isolated from the skin, gills, intestines, and
and are often considered part of the normal
muscle tissues of spoiling fish, 9,98,108.L12,147
microflora of fish."' However, no proof exists that histamine-producing bacteria are
part of the normal microflora of freshly caught fish. The enteric bacteria usually as-
sociated with histamine formation such as P. morganii and K. pneumoniae would not
be expected to be part of the normal microflora of seawater. The microflora of fish
usually reflects the microflora of their aquatic environment. 14' The typical microflora
of freshly caught marine fish include Pseudomonas, Achromobacter, Flavobacterium,
Vibrio, Micrococcus, Bacillus, and coryneforms.148IS0 Enteric bacteria are rarely
found. 148 C. perfringens, a histamine-producing species, has been found in coastal
marine sedimentsIs1 and in fish on several occasions. 1 1 2 . 1 5 1 Histamine-producing bac-
teria could only be isolated from one of ten frozen skipjack tuna despite the use of a
technique that would have provided good recovery of such bacteria from frozen fish.147
This study seems to indicate that histamine-producing bacteria are not part of the
normal microflora of tuna. Therefore, the possibility exists that histamine-producing
bacteria are not part of the normal microflora of fish but instead represent post-catch-
ing contamination.'47The microbiology of freshly caught tuna will have to be assessed
to determine the validity of this hypothesis.
Post-catching contamination with histamine-producing bacteria may occur at several
levels: aboard the fishing vessel, at the processing plant, in the distribution system
(fresh and frozen fish), and at the level of the user. Contamination during the handling
of canned tuna for the preparation of tuna salad in a restaurant was implicated in one
German outbreak.6' Restaurant contamination could be particularly important with
raw tuna.
If the histamine-producing bacteria arise from post-catching contamination, then
histamine formation could be controlled to some extent by improved hygienic prac-
tices. Further research is needed to determine the origin of the histamine-producing
bacteria, but improved sanitation is probably a desirable goal in any case.
4. Control of Histamine Formation in Fermented Foods

Virtually no research has been performed on methods for the control of histamine
formation in fermented foods. The histamine-producing lactobacilli are likely to be
naturally present in milk on occasion. However, the factors leading to their preferential
growth and subsequent histamine formation in cheese have not been determined. Swiss
cheese may be frequently implicated, because milk does not receive a full pasteuriza-
tion treatment before the production of Swiss Prolonged aging periods may
also play a role in histamine formation in Poor quality milk may also enhance
histamine formation. l S 2 Fermented herring contains high quantities of histamine OC-
casionally as noted earlier. Fermented mullet may also possess large amounts of hista-
mine.” The bacteria involved in histamine formation in fermented fish are not known,
and methods for the control of histamine formation during the fermentation process
have not been studied.
V . ANALYTICAL METHODS FOR DETECTION OF HISTAMINE
A. Introduction
Numerous methods exist for the analysis of histamine, although only a few of these
procedures were specifically developed for the detection of histamine in foods. The
earliest methods for histamine analysis were bioassay techniques,Is3 but these methods
have been largely supplanted by simpler and more accurate chemical assay methods.
Among the more popular methods for histamine analysis are the fluorometric, enzy-
matic, and chromatographic procedures.
B. Fluorometric Methods
The officially accepted method for the analysis of histamine in foods in the U.S. is
a fluorometric procedure that involves subjecting food extracts to an anion exchange
procedure to remove interfering materials, derivatizing the histamine with o-phthalal-
dehyde, and measuring the fluorescence of the resulting compound. l S 4 This method
was developed by Staruszkiewicz et aLZoand has been subjected to collaborative
s t ~ d y . ”Replicate
~ analysis of tuna agreed within 1 mg for samples containing 10 mg
histamine per 100 g and within 12 mg for samples containing 100 mg histamine per 100
g.’O Recoveries were >90% at 10 mg/100 g and >83% at 100 mg/100 g.’O The collab-
orative studies indicated excellent agreement between laboratories with recoveries av-
eraging 99% with a range of 91 to 107%.’55 The method is simple, reproducible, and
sensitive.
The fluorometric detection of histamine following its condensation with o-phthal-
aldehyde was originally developed by Shore et a1.,156.157 and it revolutionized the anal-
ysis of histamine in biological samples. The procedure was, however, not entirely spe-
cific for histamine; interference was noted by histidine, histidyl peptides, and other
amines including spermine and spermidine. ls7- Is9 Various procedures were developed
to overcome these interference problems. Spermidine interference could be eliminated
by performing the condensation reaction at -20°C,160 but the analysis time was length-
ened greatly. Modifications involving ion exchange chromatography to remove the
interfering substances proved more S U C C ~ S S ~ U 163 ~ .The
~ ~ method
~ ’ ~ ~ of
~ ~the
~ ~Associa-
tion of Official Analytical Chemists (AOAC) employs anion exchange, lS4 but cation
exchange resins work equally well for the removal of the interfering substances.’61 163
Histidine is probably the primary interfering substance in food extracts. The cationic
exchange procedure with fluorometric detection of histamine using o-phthalaldehyde
is the currently accepted procedure in the Federal Republic of Germany. ’’
An alternative procedure for histamine analysis in foods uses sequential extractions
to remove interfering Food extracts are diluted, made alkaline with 5 N
NaOH, saturated with Na2C0,, and extracted sequentially with n-butanol and 0.1 N
HC1. The acid phase is assayed for histamine with o-phthalaldehyde. This method is
currently used widely in Great Britain for the analysis of histamine in fish."
o-Phthalaldehyde is not the only fluorometric reagent that has been attempted for
the analysis of histamine in foods, but it is preferable to the others especially in terms
of its specificity.1s8 The fluorometric method with o-phthalaldehyde has been auto-
mated,165,166 but the automated procedures have not been applied to food analysis.
C. Enzymatic Methods
Several enzymatic methods have been developed for the analysis of histamine in
blood and other biological ~ a m p 1 e s . I1~6 9~The

. methods utilize the enzyme, histamine-
N-methyltransferase (HMT) and radioactive S-adenosylmethionine. Both single- and
double-isotope enzyme assays have been developed. The sensitivity of these assays is
generally higher than for the fluorometric methods. However, these methods have not
been widely used in the analysis of histamine in foods.
D. Chromatographic Methods
Chromatographic methods for histamine analysis generally fall into two categories:
simple, semiquantitative methods and more elegant, quantitative procedures. The se-
miquantitative techniques are usually based on thin-layer chromatography (TLC) while
the more elaborate methods involve gas-liquid chromatography (GLC) or high pressure
liquid chromatography (HPLC). The TLC methods have the advantage that they do
not require any expensive laboratory equipment. Equipment costs are greater for the
fluorometric methods, enzymatic methods, GLC, or HPLC, and this type of equip-
ment may not always be available.
Numerous TLC systems have been devised for the analysis of histamine in foods.
Lieber and Taylor170compared various TLC systems for histamine analysis in foods
and concluded that methano1:ammonia (20: ,)I7, and ch1oroform:methanol:ammonia
(2:2:1) were the best solvent systems. Silica Gel G was an adequate stationary phase.
Numerous samples can be analyzed simultaneously on a TLC plate. Lieber and Tay-
also compared various spray reagents for their specificity in the detection of
histamine on TLC plates. O-Dia~etylbenzene"~ and f l u o r e ~ c a m i n ewere
~ ~ ~the
. ~ most
~~
specific reagents, but ninhydrin was perhaps the most convenient spray to use.172O -
Phthalaldehyde has also been used as a spray reagent for TLC plates. 1 7 6 . 1 7 7 Other TLC
methods involve the derivatization of histamine and other amines in the sample fol-
lowed by separation of the derivatized amines; dansylated derivatives have been used
for e x a r n ~ 1 e . These
l ~ ~ systems have never been applied to the analysis of histamine in
foods. Paper chromatography has been used less frequently, but an ascending chro-
matography system using 2-methyl-propan-2- ohmethyl ethyl ketone:30% ammo-
nia:water (50:30: 10: 10) has been deve10ped.I~~
Several gas chromatographic (GC) procedures have been developed specifically for
histamine.180Histamine must be converted into some volatile derivative that can be
separated by GC. Examples have included heptafluorobutyryl derivatives with flame
ionization, electron capture, or mass spectrometric detection,180.181 trimethylsilyl deriv-
atives, with flame ionization detection,18zcombined derivatization with 2,6-dinitro-4-
trifluoromethylbenzene sulfonic acid and trimethylsilyl ethers with electron capture
~ perfluoropropionyl derivatives with electron capture detection.Is4 A
d e t e ~ t i o n , ' "and
problem with some of the approaches for derivatization of histamine has been incom-
plete elution from the columns and extensive tailing.180.184 With one exception,184these
methods have not been evaluated for the analysis of histamine from foods.
High-pressure liquid chromatography (HPLC) has also been adapted to the analysis
~ ~or
of histamine. Precolumn derivatization with ~ - p h t h a l a t e '190 - dansyl chloride191- 194
has been used successfully. An ion-moderated partition HPLC method has also
been deve10ped.I~~ Post column derivitization with n i n h y d ~ i n ' ~ ~or
- ' ~o-phthalalde-
'
hyde199.200using commercial amino acid analyzers has also been applied to histamine
analysis. Negative chemical ionization mass spectrometry has been used t o detect his-
tamine in biological samples after liquid chromatography of fluorescamine deriva-
tives.201A few of these techniques have been used successfully in the analysis of hista-
196.200 Usually, HPLC and GC procedures offer the additional
mine in foods.185.186.193
advantages of detecting other amines in the food samples.
V I . TOXICOLOGY
A. Evidence for Histamine as the Causative Agent

Compelling evidence exists to implicate histamine as the causative agent in this type
of food p o i s ~ n i n g . ~ High
. ' ~ . ~levels
~ of histamine have been found in the food sampIes
implicated in outbreaks, when such samples were available. The symptoms noted
among the patients in these outbreaks are consistent with the involvement of histamine,
since they mimic the symptoms involved in allergic reactions. However, the most con-
vincing evidence is the efficacy of antihistamines in counteracting the symptoms ob-
served in cases of suspected histamine poisoning.
While the evidence implicating histamine as the causative agent is quite strong, Jap-
anese investigators at one time isolated a histamine-like substance called saurine from
spoiled saury.202 Saurine was later identified as merely the phosphate salt of hista-
mine.79
B. Pharmacological-Toxicological Actions of Histamine

1. Zntroduction
Histamine possesses powerful biological actions. Histamine is the chemical that is
released from mast cells during an allergic reaction, and it serves as a primary mediator
of the immediate symptoms noted in allergic responses. The mediation of allergic re-
actions is an example of the toxic potential of histamine.
Histamine also has important physiological functions. It is involved in the regulation
of such critical functions as the release of stomach acid. In small physiological doses,
histamine is a necessary and desirable substance. When the dose of histamine is greatly
increased, then histarnine begins to exert its toxic effects.
2. H , and Hz Receptors
Histamine exerts its effects by interacting with receptors on cellular membranes.
Two types of histamine receptors, known as the H , and H I receptors, exist. These two
types of histamine receptors can be differentiated on the basis of the effects of specific
agonists and antagonists. 2-Methylhistamine, for example, is active on tissues with H I
receptors, while 4-methylhistamine is active on tissues with H2 The H I
receptors were discovered first, and a whole series of antihistaminic drugs were devel-
oped that blocked H , , but not H 2 receptors. Clinically useful H,-blockers are deriva-
tives of ethanolamine, ethylenediamine, alkylamine, piperazine, and phenothiazine.'
These agents are useful in the treatment of allergic reactions and histamine poisoning.
The classical antihistamines block many but not all of the manifestations of allergic
reactions.8
The lack of complete effectiveness of the H,-antihistamines led to the theory that a
second type of histamine receptor existed.' The proof of the existence of the H Zrecep-
tors came with the development of specific H 2 antagonists. Burimamide was the first
of these H2 It was later followed by more effective agents such as me-
tiamideZo4and ~ i m e t i d i n eThe
. ~ ~release
~ of stomach acid is primarily a function of the
H, receptors so cimetidine is widely used to treat illnesses requiring the control of

gastric acid secretion such as duodenal ulcers and Zollinger-Ellison syndrome. Cime-
tidine is also useful in the treatment of histamine p o i ~ o n i n g . ' ~
3. Tissue Stores of Histamine

Despite its toxicity, histamine is not a foreign substance to the body. However, most
of the histamine is stored in specialized cells where its release is regulated. The major
repository for histamine i n the body is the mast cell.' Mast cells are found in most
tissues, but differences may exist in the characteristics of the cells from various tis-
sues.2o6Another repository for histamine is the blood basophil. Nonmast cell stores
for histamine may also exist.8 Mast cells and basophils synthesize histamine and have
intracellular secretory granules that contain large quantities of histamine. Antigens can
interact with antigen-specific IgE molecules on the membrane surfaces of these cells
triggering degranulation of the mast cells and release of the histamine. Antigen-me-
diated histamine release occurs during allergic responses.
4. Toxicological Responses to Histamine

Most of the principal physiological actions of histamine were noted in the early
experiments of Dale and laid la^.^^'^^^* Although the predominant effects varied be-
tween species, many of the symptoms of histamine poisoning as noted earlier (Table 1)
were observed in their animal experiments especially when higher doses were adminis-
tered.
Some of the more common symptoms of histamine poisoning result from the actions
of histamine on the cardiovascular system.ls These actions involve both H I and H 2

receptors.8 Histamine causes dilatation of the peripheral blood vessels and capillaries
via interaction with both H , and H, receptors.8 In man since H, receptors predominate
in the arteries, histamine also induces arteriolar dilatation.' In other species where H I
receptors predominate in the arteries, histamine causes arteriolar constriction, al-
though the peripheral dilatation usually predominates eliciting an overall depressor
response.8 In man, the actions of histamine on the vascular system result in hypoten-
sion, flushing, and headache. Histamine also induces increased capillary permeabil-
ity.Z08.209The loss of plasma through the capillary endothelium produces symptoms
such as edema, urticaria,.hemoconcentration, and increased blood viscosity. Shock can
result from administration of very high doses of histamine.209The effect on capillary
permeability is mediated by both H I and Hz receptor^.^^^^^'^
Histamine exerts a direct stimulatory action on the heart.Z11Histamine increases
heart contractility and increases the rate and strength of the contractions. The effects
of histamine on the heart might account for the palpitations noted by some persons
experiencing histamine poisoning.
Histamine can cause either contraction or relaxation of extravascular smooth mus-
cles. Contraction is mediated b y H I receptors, while relaxation is associated with H2
receptors.'s In man, the predominant action of histamine on extravascular smooth
muscles is contraction.*s This smooth muscle contraction is most often noted in the
bronchi and intestines. In histamine poisoning, the contraction of intestinal smooth
muscle is particularly apparent, because the histamine enters the gastrointestinal tract
initially. Contraction of intestinal smooth muscle leads to the abdominal cramps, diar-
rhea, and vomiting often noted in cases of histamine poisoning. Other mechanisms
may also be involved in these symptoms, but these mechanisms are not clearly under-
stood .I5
Gastric acid secretion is also regulated by histamine through H2receptors on the
parietal cells.213Doses of histamine below those required to lower blood pressure will
stimulate acid release. The importance of this action of histamine to the symptoms
observed in cases of histamine poisoning is unclear.
Histamine is also a potent stimulant of both sensory and motor neurons." This
stimulation may be important in producing the pain and itching that frequently accom-
pany the urticaria1 lesions in histamine poisoning. This neural stimulation is mediated
by H, receptors. Histamine may also be a neurotransmitter in the central nervous sys-
tem, but more evidence will be needed to confirm this possibility.8
C . Human and Animal Oral Challenge Studies

While intravenous administration of histamine causes immediate effects in all ani-
mals including humans, the results of oral challenge studies have been inconsistent.
Oral administration of histamine in spoiled tuna to pigs and dogs elicits an emetic
r e s p o n ~ e . ~ 'Histamine
~ . ~ ' ~ alone provoked emesis in pigs In rats, intraduodenal
injection of histamine produced only transient hypotension.2's A similar response was
noted with cats.z1SHowever, when a histamine-containing yeast extract was injected
intraduodenally into cats rather than histamine, a wider variety of effects, including
increased volume and acidity of stomach acid, increased hematocrit and limb volume,
and enhanced electromyographic activity, was Chicks displayed a de-
creased growth rate when fed spoiled tuna containing histamine by comparison to un-
spoiled tuna.2L6
Weiss et al.2i7observed that orally administered histamine had no effect on humans.
They administered up to 180 mg of histamine orally without noticeable effects, while
intravenous administration of only 7 pg of histamine produced vasodilation and an
increased heart rate.zi6GranerusZ'*noted a similar lack of effect of orally administered
histamine, although the upper dose in his studies was only 67.5 mg. Motil and Scrim-
shawZi9succeeded in producing some mild effects in humans by orally administering
100 to 180 mg of histamine in combination with good quality tuna. The mild and
transient symptoms noted in this study included headache, facial flushing, vertigo, and
nausea. While these symptoms are consistent with histamine poisoning, they would
occur in only very mild cases. Also, the doses needed to provoke these mild reactions
were several times higher than the doses producing more severe symptoms when con-
sumed with spoiled fish. Human challenge studies have not been performed with his-
tamine added to spoiled fish.
D. The Paradox
Compelling evidence exists for the involvement of histamine as the causative agent
o f this type of food poisoning. The efficacy of antihistamine therapy would be partic-
ularly difficult to reconcile with any other explanation. Yet, the illness has been vir-
tually impossible to reproduce in oral challenge studies with human volunteers. This
paradox between the lack of toxicity of pure histamine and the apparent toxicity of
even smaller doses of histamine in spoiled fish or certain types of cheese could be
explained by the existence of potentiators of histamine toxicity in the spoiled fish.
These potentiators would act to decrease the threshold dose of histamine needed to
provoke an adverse reaction in humans challenged orally.
E. Evidence for Potentiation of Histamine Toxicity

The existence of food-borne potentiators of histamine poisoning has not been firmly
established, but has been suggested by the results of several studies. Miyaki and Hay-
ashiZZ0isolated an unidentified synergistic factor from dried seasoned saury. Subse-
quently, Hayashi"' reported that trimethylamine, trimethylamine oxide, agmatine,
and choline could potentiate the contractile effect of histamine on guinea pig uterus.
Kawabata et a1.222disputed this observation and found that trimethylamine and tri-
methylamine oxide were ineffective in potentiating the action of histamine on guinea
pig uterus. Earlier, Kawabata et al.202had isolated saurine, a chemical with similar
properties to histamine but with distinct chromatographic behavior. Although saurine

was later shown to be an artifact of the separation t e ~ h n i q u e , ’this
~ report became the
foundation for widespread speculation about the existence of potentiators of histamine
poisoning. MongarZz3demonstrated that short-chain aliphatic diamines, such as cadav-
erine and putrescine, could potentiate the histamine-induced contraction of guinea pig
ileum. These results were later extended to show that cadaverine also potentiated the
histamine-induced contraction of guinea pig trachea and Parrot and NicotZz5
were the first to actually demonstrate that the oral toxicity of histamine could be po-
tentiated. When putrescine was orally administrated t o guinea pigs prior to histamine,
the lethality of histamine was enhanced, although rather large concentrations of pu-
trescine were required.Z2sCadaverine can also enhance the lethality of orally adminis-
tered histamine to guinea pigs, and much lower concentration of cadaverine are re-
quired for this potentiating effect.226Feeding studies with Japanese quail showed that
the inhibition of growth rate was dependent on the presence of histamine and other
unidentified toxic substances in spoiled tuna.2z7While dogs did not vomit following
oral administration of histamine alone at doses of 20 mg/kg, the combination of his-
tamine with spoiled tuna did elicit emesis even at histamine doses of 1 t o 10 mg/kg.’14
Several of the substances identified as possible potentiators including cadaverine and
putrescine are known to occur in spoiled fish.’841 9 3 , 2 2 8 Whether the concentrations of
these suspected potentiators in spoiled fish are sufficient to enhance the toxicity of
histamine to humans remains to be determined. Obviously, other, as yet unidentified,
potentiators may also exist.
F. Histamine Metabolism and Its Inhibition

1 . Histamine Metabolism
The lack of toxicity of orally administered histamine can probably be explained by
the presence of histamine-metabolizing enzymes in the intestinal tract that prevent the
absorption of unmetabolized histamine into the circulation. The major pathways for
histamine metabolism are depicted in Figure 2. Histamine is primarily metabolized by
two enzymes, diamine oxidase (DAO, histaminase, EC 1.4.3.6)and histamine-N-methyl-
transferase (HMT, E C 2.1.1 .8).8.15.229 231 The ultimate end products of histamine me-
tabolism are excreted in the urine. HMT converts histamine into (W-methylhistamine
(W-MH). W-MH is converted by another enzyme, monoamine oxidase (MAO, EC
1.4.3.4) into W-imidazoleacetic acid (NT-MIAA). DAO converts histamine into imi-
dazoleacetic acid (IAA), which can be conjugated with ribose before excretion. Trace
amounts of Nu-methylhistamine (N”-MH) and N u , No-dimethylhistamine ( N ” ,NO-
MH) have been found in human urine,8 but little is known about the origin of these
metabolites or the enzymes involved. Histamine can also be acetylated to form N -
acetylhistamine (N-AH) presumably through the action of intestinal b a ~ t e r i a . ~ . ~ ~ ~ . ~ ~ ~
The relative importance of the HMT and DAO pathways varies among species. The
oxidative deamination pathway predominates in rats and guinea pigs.23’The methyla-
tion pathway is of prime importance in humans, mice, cats, pigs, and hamster~.’~’ The
metabolism of histamine is also dependent t o some extent on the route of administra-
tion. Intravenously or intradermally injected histamine in humans is metabolized pri-
marily by the methylation pathway with excretion in the ~ r i n e When . ~ histamine
~ ~ ~ ~ ~ ~
is administered orally to humans, only 68 t o 80% of a radioactive dose could be re-
covered in the urine.233Some histamine remained in the feces and additional amounts
were catabolized by intestinal bacteria and exhaled as l4COZfrom the lungs.233The
nature of histamine metabolism also varies among different tissues in an animal. Meth-
ylation predominates in most mouse tissues, while oxidative deamination predominates
in most tissues of the rat.23’.z34 In the pig, methylation predominates in the liver and
lung, while oxidative deamination predominates in the intestinal m u c o ~ a In. ~general,
~~
IMIDAZOLE ACETALDEHYDE N‘-METHYLMSTAMINE
IMIDAZOLEACETIC ACID N‘-METHYLIMIDAZOLEACETIC ACID

RlBOSlDE
FIGURE 2. Metabolic pathways for histamine.
the highest rates of histamine metabolism are found in the intestines, liver, kidney,
lung, and spleen. Comparatively few studies have been performed on the distribution
of the histamine-metabolizing enzymes in humans. Recently, Hesterberg et al. 236 dem-
onstrated that HMT was widespread in human tissues with the order of activity being
liver >> colon > spleen > lung > small intestine > stomach. Although kidney was not
included in that study, it is also known to possess methylating In contrast,
DAO was localized almost exclusively in the small This differential distri-
bution of the histamine-metabolizing enzymes may account, in part, for the differences
in metabolism of orally and intravenously administered histamine. In rats, histamine
induces the release of diamine oxidase into the lymph from the intestinal mucosa which
may be a protective response to reduce toxic levels of free histamine in the intestinal
Histamine metabolism can be influenced by the diet. Food intake elevates the uri-
nary excretion of histamine, W-MH, IAA, and IAA-riboside for 1 to 3 hr after the
This elevated excretion was noted even after a protein-deficient meal suggest-
ing that gastric secretion of histamine was triggered by food intake and that the in-
creased urinary excretion of histamine and its metabolites originated from the stom-
a ~ h However,
. ~ ~ ~ Keyzer et al.240found that excretion of N'-MH was elevated after
high protein meals by comparison to low protein or very low protein meals. No effect
of dietary protein level was noted on excretion of NT-MIAA.240 G r a n e r u ~was
~ ~among
~
the first to note the effect of diet on histamine metabolism. His studies indicated that
the variability in urinary excretion of histamine, W-MH, and N'-MIAA observed in
human subjects from one day to the next, was the result of dietary influences. A stand-
ardized diet low in histamine and nearly free of bacteria produced a consistent excre-
tion pattern in his Granerus also noted that cigarette smokers had higher
excretion rates for histamine and its metabolites than Treatment with
broad-spectrum antibiotics to kill the majority of the intestinal bacteria resulted in
slightly decreased urinary excretion of N'-MH and N'-MIAA suggesting that some
histamine is synthesized by anaerobic intestinal b a ~ t e r i a . " ~
Histidine metabolism can also be altered by various disease states. In patients with
systemic mastocytosis and urticaria pigmentosa, the levels of histamine and N-MIAA
in the urine were considerably increased, and iV-MIAA excretion could be correlated
with disease Histamine metabolism may be more efficient in mastocytosis
patients, since the molar ratio of N-MIAA to N-MH was significantly higher in these
patients by comparison to Urinary excretion of N-MIAA, N-MH, and
histamine was enhanced by positive bronchial challenges in asthmatics.245A single pa-
tient with a gastric carcinoid tumor excreted elevated amounts of histamine, N - M H ,
and N-MIAA, while four patients with intestinal carcinoid tumors excreted an unusual
methylated form of Urinary excretion of histamine and its metabolites
was dramatically elevated in patients with chronic myelocytic leukemia or polycy-
themia vera.247.248 Histidinemia, an inborn error resulting from the absence of histidine
ammonia-lyase (EC 4.3.1.3), is also associated with increased excretion of histamine
and its metabolite^.^^^ Patients with altered histamine metabolism may be more suscep-
tible to histamine poisoning, although this remains to be proven. Certainly, exogenous
histamine would exacerbate diseases such as systemic mastocytosis.
One impediment to the study of histamine metabolism has been the lack of simple
and sensitive assay procedures for the various histamine metabolites. Most of the stud-
ies on the metabolism of histamine in animals were performed with the isotope dilution
technique of Schayer."' While accurate, the method is quite time-consuming and re-
quires large quantities of rather expensive carrier substances. Chromatographic sepa-
rations and derivatization procedures were complicated by the existence of both acidic
and basic metabolites of histamine. Hence, some of the chromatographic methods are
useful for only one or two of the metabolites. Shifrine and ZweigZs1developed a paper
chromatographic procedure capable of detecting all of the major histamine metabo-
~ ~ ~ a two-dimen-
lites. This method is hampered by lack of sensitivity. E l i a s ~ e ndevised
sional paper chromatographic method, but it was only semiquantitative. Schwartz-
mannZs3utilized TLC for the analysis of histamine and its major metabolites. A
derivatization procedure producing fluorescent products was used for detection. Schip-
pert et al.254used prederivatization with dansyl chloride before TLC but this procedure
is useful primarily for the basic metabolites. Specific TLC procedures for N-MHZSS
and N-MIAA2s6were also developed but were found subject to considerable error.244
Ion exchange chromatography on an amino acid analyzer has been used for the anal-
ysis of histamine and its metabolite^.'^^ Since histamine and its metabolites d o not
absorb light in the useful ranges of an amino acid analyzer and since postcolumn de-
rivatization procedures would not be useful for all metabolites, the identification of
the metabolites in the fractions required the collection of fractions, scintillation count-
ing, and the availability of radioactive standards. Histamine and its basic metabolites
can be detected by liquid chromatography after dan~ylation’~’ or with an amino acid
analyzer using postcolumn derivatization with o-phthalaldehyde.Ig9 Tsuruta et al.’”
used precolumn derivatization with o-phthalaldehyde and HPLC for the determina-
tion of histamine and W-MH. A similar procedure was developed for the same pur-
pose by Robert et al.259A reverse-phase, ion-pair HPLC procedure has recently been
devised for the simultaneous analysis of histamine and all of its principal metabo-
lites.260Specific H P L C and G C procedures have been devised for the analysis of N‘-
MIAA261 263 and NT-MH.264.265
2. Inhibition of Histamine-Metabofizing Enzymes

HMT is very selective for histamine and requires S-adenosylmethionine as a methyl
donor. HMT is inhibited by analogues of S-adenosylmethionine, such as S-adenosyl-
homocysteine.266Other HMT inhibitors include antimalarial drugs (e.g., quinacrine,
chloroquin, and amodiaquin) and numerous agonists and antagonists of the H , and
H, 2 7 1 HMT is also subject to substrate inhibition by high concentrations
o f histamine. The type of inhibition (competitive, uncompetitive, noncompetitive) var-

ies depending on the inhibitor.269Barth and L o ~ e n z ’studied
~~ several imidazole inhib-
itors of HMT, and differentiated them into two groups. One group inhibited HMT a t
all concentrations, while the other group inhibited HMT at high concentrations, but
activated the enzyme at low concentrations. Some food-borne substances are inhibitors
o f HMT including tyramine, p-phenylethylamine, tryptamine, and agmatine.z72
DAO is not selective towards histamine but also oxidizes other diamines such as
putrescine. Many inhibitors of DAO have been identified.273.274 A premier example is
aminoguanidine, a noncompetitive inhibitor of DA0.Z70Semicarbazide, carbonyl re-
agents, diamines, guanidine, and imidazole derivatives have all been identified as DAO
inhibitors.224Many antihistaminic drugs are DAO inhibitor^.''^ Several compounds
once classified as specific M A 0 inhibitors are known t o inhibit DAO These
substances include tranylcypromine, isoniazid, and pargyline. The nonspecific M A 0
inhibitors are effective DAO inhibitors, while the type A M A 0 inhibitors are ineffec-
tive and the type B M A 0 inhibitors are somewhat effective as DAO inhibitor^.'^^ DAO
is also subject to substrate inhibition when certain diamines including histamine are
used as ~ u b s t r a t e s . ’A~ number
~ ~ ~ ~ ~of foodborne substances are inhibitors of DAO
including anserine, carnosine, agmatine, thiamin, cadaverine, and t ~ r a m i n e . ~ ~ ~
M A 0 is also important in histamine metabolism because of its oxidation of N - M H .
M A 0 is a nonspecific enzyme capable of oxidizing most monoamines.zso This enzyme
exists in several functionally distinct forms.281MAO-A acts on some monoamines such
as norepinephrine and serotonin, while MAO-B acts on others such as phenylethyl-
amine.281Some monoamines, such as dopamine can be oxidized by both MAO-A and
MAO-B.28’ Numerous selective and nonselective inhibitors of M A 0 are known.’80.281
Imrie et evaluated the effect of selective and nonselective M A 0 inhibitors on the
metabolism of intraduodenally infused histamine. Nonselective M A 0 inhibitors such
as mebanazine and nialamide elicited an increase in the circulating levels of histamine
and N - M H , while the selective M A 0 inhibitors such as deprenyl and chlorgyline were
without effect unless very high doses were infused.”’
G . Potentiation via Enzyme Inhibition

Since the majority of an oral dose of histamine is excreted in the urine as histamine
metabolite^,^^^,^^^ the metabolism of histamine probably serves as a detoxification
mechanism. The small intestine and the liver are particularly rich sources of the hista-
mine-metabolizing enzymes, and these tissues would play the primary role in the catab-
olism of orally ingested histamine.
The hypothesis that histamine toxicity could be potentiated by inhibition of the his-
tamine-metabolizing enzymes was first put forth by Taylor and Lieber27zwho showed
that rat intestinal HMT and DAO could be inhibited by certain food-borne amines,
including some food-borne amines known t o occur in spoiled fish.193.z28 Many of these
amines inhibited only one of the two enzymes but several including cadaverine and
aminoguanidine could inhibit both HMT and DA0.272Although mixtures of these
amines were not evaluated, they would be predicted to be effective inhibitors of intes-
tinal histamine m e t a b o l i ~ m . 'This
~ hypothesis was supported by earlier work that dem-
onstrated a potentiation of the histamine-induced contractions of smooth muscle by
DAO inhibitor^.^^^^^^^ Also, prior administration of aminoguanidine, a potent DAO
inhibitor, abolished excretion of radioactive IAA, increased excretion of RT-MH, and
had little effect on excretion of histamine and N-MIAA in human Also,
isoniazid, an antituberculosis agent and known inhibitor of DAO, has been implicated
in several outbreaks of histamine poisoning. 17.76.82 8 5
The in vitro experiments of Lyons et al.z83and the in vivo studies of Hui and Tay-
lorzs4 provide further evidence that the potentiation of histamine toxicity operates
through the inhibition of histamine catabolism. In the experiments of Lyons et al.,z83

rat ileal segments were perfused in vitro with either histamine alone or histamine plus
equimolar amounts of cadaverine, aminoguanidine, or anserine. In the presence of
cadaverine or aminoguanidine, more unmetabolized histamine was transferred from
the lumen to the serosal fluid despite the fact that the total transport of radioactivity
was unchanged. These results indicate that inhibition of intestinal histamine metabo-
lism was effective in potentiating the intestinal uptake of histamine. However, the in
vitro experiments did not take into account the possible effects of extraintestinal his-
tamine metabolism. Absorbed histamine would first pass through the liver, and inhi-
bition of liver histamine-catabolizing enzymes would be necessary to allow systemic
distribution of unmetabolized histamine. Hui and Taylorzs4 orally administered I4C-
histamine to rats either alone or simultaneously with suspected food-borne (cadaver-
ine, putrescine, tyramine, and @-phenylethylamine) or pharmacologic (aminoguani-
dine, isoniazid, and quinacrine) potentiators of histamine toxicity. When histamine
was administered alone, 80% of the radioactive dose was recovered in the urine within
24 hr with 60.6% as IAA, 8.6% as RT-MIAA, 7 . 3 % as N - M H , and 4.5% as N-AH.
When the suspected potentiators were administered simultaneously with the histamine,
an increased amount of unmetabolized histamine and a decreased amount of histamine
metabolites were excreted in the urine. Total excretion of imidazole compounds was
not markedly altered by the different treatments. These results provide evidence that
suspected potentiators can alter histamine metabolism in vivo and likely prolong the
half-life of unmetabolized histamine. The pattern of metabolite excretion varied be-
tween the different inhibitors. DAO inhibitors were most effective since oxidative
deamination is the primary metabolic pathway in Although the methylation
pathway is known to predominate in man,231DAO is the predominant enzyme in hu-
man small and oxidative deamination was the main pathway for metabo-
lism of orally administered histamine in man.233Therefore, the results obtained in rats
may well be applicable to the human situation, although it would be interesting to
repeat these studies in other species, especially those species with greater methylating
capacities than the rat.
H . Other Possible Mechanisms of Potentiation

Another possible mechanism of potentiator action, known as the barrier disruption
hypothesis, has received considerable attention. This hypothesis was first proposed by
Parrot and NicotzZswho suggested that potentiators might interfere with the protective
actions of intestinal mucin. M u c h is known to bind and Parrot and Ni-
cotzz5suggested that this binding was essential to prevent the intestinal absorption of
histamine. Potentiators such as putrescine and cadaverine may bind preferentially t o
intestinal mucin preventing its binding to histamine and facilitating the absorption of
histamine.22s~286
The barrier disruption hypothesis predicts that the total transport of imidazole com-
pounds across the intestinal barrier would increase in the presence of potentiators. This
hypothesis would also predict no alteration in the ratio of histamine to its metabolites
in the presence of potentiators. In fact, Lyons et al.283found that the overall transport
of radioactivity across the intestinal wall was unchanged in the presence of potentia-
tors. Similarly, Hui and Taylorzs4 found no change in the 24-hr excretion of imidazole
compounds after administration of histamine plus potentiators. The ratio of histamine
to its metabolites was altered in both the in vitro and in vivo experiments.z83~284 These
results do not support the barrier disruption hypothesis.
The barrier disruption hypothesis is supported by the experiments of Jung and Bjel-
danes,zs6although these experiments appear to be f l a ~ e d . The ' ~ ~intestinal
~ ~ ~ transport
of total radioactivity was potentiated by incubation of equimolar amounts of cadav-
erine and ''C-histamine in noneverted gut sacs over a 2-hr period of incubation.z86
Additionally, the ratio of histamine to its metabolites was not altered in the presence
o f cadaverine. These results are in direct conflict with those of Lyons et al.zs3However,
Plattner et a1.2870showed that everted gut sacs are viable for only 3 0 min in an oxygen-
ated, nutrient medium. The noneverted gut sacs employed by Jung and BjeldanesZs6
would be predicted to be less viable than everted gut sacs because of the diminished
exposure of the epithelial cells to oxygen and nutrients. Despite this potential for dam-
age to the intestinal epithelial membranes, Jung and Bjeldaneszs6 used a 3-hr incuba-
tion period with the noneverted gut sacs and provided no histological evidence of tissue
integrity. Lyons et al.2s3found that the noneverted gut sacs of rats suffered extensive
tissue damage after only 30 min of incubation.
Several other pieces of evidence tend to support the barrier disruption hypothesis.
The binding of histamine to m u c h is inhibited in vitro by spermine, spermidine, pu-
trescine, cadaverine, and a basic extract of tuna.z8sHowever, the inhibition required
rather high amine concentrations, and the tuna extract caused only a 23% inhibition
of binding.2ss Since each mole of intestinal mucin can bind 2.5 mol of histamine,'*' the
vast excess of mucin over histamine in the gastrointestinal tract would seem to indicate
that this inhibition of binding would play a secondary role in the potentiation of his-
tamine toxicity. Histamine can disrupt the tight intercellular junctions between intes-
tinal goblet cells and neighboring epithelial cells.z87This disruption of the integrity of
the intestinal barrier could contribute to an increased absorption of histamine. How-
ever, rather high histamine concentrations were required to disrupt these intercellular
No evidence was found for such disruptions in the in vitro intestinal per-
fusion studies with histamine and/or the poter~tiators.'~~
I . Implications of Potentiation
The threshold toxic dose for histamine in foods is not precisely known. The varia-
bility in histamine levels in a spoiled fish9,Iz9make estimates of the toxic threshold
difficult to obtain. Simidu and HibikiZS8estimated the threshold toxic dose for hista-
mine in fish at approximately 60 mg/100 g. However, their methods were not terribly
precise. The U.S. Food and Drug Administration has recently established a hazard
action level for histamine in tuna of 50 mg/100 g based on the experience acquired
from the investigation of numerous histamine poisoning The FDA has not
yet established regulatory limits for histamine in other fish or cheese.
The existence of potentiators could alter the threshold toxic dose for histamine in
foods. Different foods would contain different potentiators, and the levels of potentia-
tors would also vary considerably from one food to another. Consequently, the thresh-
old toxic dose for histamine would be expected to vary from one food to another as a
function of the types and amounts of the potentiators. The types and levels of the
potentiators in foods would depend on a variety of factors including the types of mi-
croflora, the metabolic capabilities of the microflora, the natural constituents of the
food, and the conditions of spoilage. In particular, the profile of potentiators in cheese
would likely be much different from fish. Consequently, although the health hazard
associated with ingestion of tuna containing 50 mg histamine per 100 g is fairly well
established, the hazard associated with similar levels of histamine in other fish and
cheese remains t o be determined. Until the identity, levels, and potency of the poten-
tiators can be more completely elucidated, it may be premature to establish regulatory
limits for histamine in foods on the basis of any potential health hazard.
ACKNOWLEDGMENTS
The support of the College of Agricultural and Life Sciences, University of Wiscon-
sin, USDA Hatch Project No. 2788, and the food industry are gratefully acknowl-
edged.
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Histamine Food Poisoning: Toxicology and Clinical Aspects

Article in Critical Reviews in Toxicology · February 1986

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HISTAMINE FOOD POISONING:

Author: Steve L. Taylor

Referee: Ronald R. Eitenmiller

Histamine, 4-(2-aminoethyl)imidazole (Figure l), is a primary amine arising from

ious conformations of the side chain.* A slight change in pH from p H 6 to pH 7 can

11. CLINICAL ASPECTS

FIGURE 1. Formation of histamine by decarboxylation of L-histidine.

D. Treatment and Avoidance

Since the disease is self-limited, pharmacological intervention may not be necessary in

1970 5 178 Mackerel (2)

From data compiled by Ministry of Health and Welfare, Japan.”

No. of No. of Implicated food

1968 3 19 Tuna (2)

Compiled from Centers for Disease Control, Annual Sum-

histamine poisoning occurred in 1973 involving commercially canned tuna. 13.31,32This

sudden increase in reports of histamine poisoning in Great Britain appears to be related

to an increase in the consumption of mackerel and a concomitant decrease in the con-

No. of No. of Implicated food

1976 3 9 Smoked mackerel (3)

Canned mackerel (2)

1981 26 45 Smoked mackerel (10)

From Taylor, S. L., Histamine Poisoning Associated with Fish,

Lanka.17.82-85These incidents involved tuberculosis patients on isoniazid therapy, and

B. Foods Implicated in Histamine Poisoning

Common name Family Genus and species

Big-eye tuna T. obesus or Parathunnus mebachi

Indo-Pacific or striped bonito S. orientalis

the significance of this incident was underestimated by many scientists. However, in

and pepperoni are known to have high levels of histamine on occasion.

IV. FORMATION OF HISTAMINE AND ITS CONTROL

2. Bacteria Possessing Histidine Decarboxylase

histamine producer~."~ Recently, a strain of L. buchneri was isolated from a sample

to be limited to only a few strains of lactobacilli. However, this ability is possessed by

B. Control of Histamine Formation

2. Low Temperature Storage of Fish

histamine formation in fish at storage temperatures of 0 to 10°C.70.130.132.136,142.144

3 . Hygienic Practices to Avoid Contamination

4. Control of Histamine Formation in Fermented Foods

V . ANALYTICAL METHODS FOR DETECTION OF HISTAMINE

matic, and chromatographic procedures.

blood and other biological ~ a m p 1 e s . I1~6 9~The

A. Evidence for Histamine as the Causative Agent

B. Pharmacological-Toxicological Actions of Histamine

H, receptors so cimetidine is widely used to treat illnesses requiring the control of

3. Tissue Stores of Histamine

4. Toxicological Responses to Histamine

of histamine on the cardiovascular system.ls These actions involve both H I and H 2

C . Human and Animal Oral Challenge Studies

E. Evidence for Potentiation of Histamine Toxicity

properties to histamine but with distinct chromatographic behavior. Although saurine

F. Histamine Metabolism and Its Inhibition

IMIDAZOLE ACETALDEHYDE N‘-METHYLMSTAMINE

IMIDAZOLEACETIC ACID N‘-METHYLIMIDAZOLEACETIC ACID

2. Inhibition of Histamine-Metabofizing Enzymes

H, 2 7 1 HMT is also subject to substrate inhibition by high concentrations

o f histamine. The type of inhibition (competitive, uncompetitive, noncompetitive) var-

G . Potentiation via Enzyme Inhibition