Toxicology of Scombroid Poisoning - ACS Publications - American

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Toxicology of Scombroid Poisoning

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STEVE L. TAYLOR, JULIA Y. HUI, and DAVID E. LYONS

Downloaded by FUDAN UNIV on March 5, 2017 | http://pubs.acs.org Publication Date: September 19, 1984 | doi: 10.1021/bk-1984-0262.ch035

Food Research Institute, University of Wisconsin, Madison, WI 53706 Scombroid poisoning i s caused by ingestion of foods containing unusually high levels of histamine. Scombroid poisoning occurs worldwide i nallcountries where f i s h i s consumed. The evidence supporting the role of histamine as the causative agent in scombroid poisoning i s compelling. However, histamine ingested with spoiled f i s h i s much more toxic than histamine ingested in an aqueous solution. This paradox may be explained by the presence of potentiators of histamine t o x i c i t y in spoiled f i s h . Several substances, including cadaverine and putrescine, have been i d e n t i f i e d as possible potentiators of histamine t o x i c i t y that would be expected to be present i n spoiled f i s h . The mechanism of action of these potentiators has not been completely elucidated, but they appear to act by i n h i b i t i o n of i n t e s t i n a l histamine-metabolizing enzymes. This enzyme i n h i b i t i o n increases the i n t e s t i n a l uptake of unmetabolized histamine. Scombroid poisoning i s a chemical intoxication occurring after the ingestion of foods that contain unusually high levels of histamine. The incubation period for this foodborne disease i s short ranging from several minutes to several hours following ingestion. The duration of the i l l n e s s i s t y p i c a l l y only a few hours, but symptoms l a s t i n g up to several days have been reported (1.2). A variety of symptoms can occur in cases of scombroid poisoning. The symptoms can be cutaneous (rash, u r t i c a r i a , edema, l o c a l i z e d inflammation), g a s t r o i n t e s t i n a l (nausea, vomiting, diarrhea), hemodynamic (hypotension), and neurological (headache, palpitations, t i n g l i n g , flushing or burning, i t c h i n g ) . Most individuals suffering from scombroid poisoning w i l l experience only a few of these symptoms. Even in group outbreaks, i t may not be possible to observe a l l of these symptoms. 7

Current address: Cooper Biomedical/Therapeutics Division, San Jose, C A 95119

0097-6156/ 84/ 0262-0417S06.00/ 0 © 1984 American Chemical Society

Ragelis; Seafood Toxins ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

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The symptoms vary in frequency of occurrence. Merson et a l . (3), in an investigation of a large outbreak, l i s t e d nausea, cramps, and an o r a l burning sensation as the most common symptoms. Murray et a l . (4), summarizing a series of outbreaks in England, reported rash, flushing with sweating, and an o r a l burning sensation as the most common symptoms. Because the symptoms of scombroid poisoning mimic those observed in a l l e r g i c reactions, the i l l n e s s i s sometimes misdiagnosed as an allergy. Scombroid poisoning can be e a s i l y distinguished from an a l l e r g i c reaction (1). In group outbreaks, the attack rate often approaches 100%, while f i s h a l l e r g i e s are r e l a t i v e l y rare. The patients involved in outbreaks of scombroid poisoning w i l l often indicate that they have previously eaten the f i s h on many occasions without i l l e f f e c t s . Also, analysis of the remaining f i s h from an outbreak w i l l reveal high levels of histamine in the f i s h . Epidemiology of Scombroid Poisoning Complete reporting of scombroid poisoning c e r t a i n l y does not occur on a worldwide basis. Many countries do not keep s t a t i s t i c a l data on the incidence of foodborne diseases. However, even in countries with good record-keeping, scombroid poisoning i s incompletely reported for several reasons: (a) many patients do not seek medical attention for this r e l a t i v e l y mild, short-lived malady, (b) physicians often misdiagnose scombroid poisoning as food allergy or some other foodborne disease, and (c) in most countries, scombroid poisoning i s not a n o t i f i a b l e disease. Worldwide Incidence. Table 1 l i s t s the number and size of outbreaks of scombroid poisoning occurring in the United States, England, Japan, Canada, New Zealand, and Denmark during the period of 1971 through 1980. In recent years, England has experienced the largest number of outbreaks although most have been small. Japan has had the largest outbreaks and the greatest t o t a l number of cases of scombroid poisoning. Japanese outbreaks of scombroid poisoning have declined dramatically since 1980 following the adoption of s t r i c t control measures aimed at insuring that f i s h are held at 5°C or below after catching. Although less complete s t a t i s t i c s have been kept, outbreaks have also occurred in West Germany, East Germany, France, Norway, Finland, Sweden, Portugal, Poland, Czechoslovakia, Sri Lanka, Indonesia, South A f r i c a , Egypt, Turkey, A u s t r a l i a , South Korea, Hong Kong, People*s Republic of China, and Republic of China (Taiwan). Types of Fish. The f i s h most commonly implicated in these outbreaks are the so-called scombroid f i s h belonging to the families Scomberesocidae and Scombridae. These f i s h would include the many v a r i e t i e s of tuna, skipjack, bonito, albacore, mackerel, Spanish mackerel, b l u e f i s h , saury, b u t t e r f l y kingfish, and seerfish. Tuna, skipjack, and mackerel are the most commonly involved scombroid fish. Several types of non-scombroid f i s h can also be incriminated i n outbreaks of scombroid poisoning. Thus, scombroid poisoning i s a


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TABLE I. Number and Size of Outbreaks of Histamine Poisoning Occurring i n Certain Countries from 1971-1980

Year

Country

1971 1972

Japan Japan United States Japan New Zealand United States Japan New Zealand United States Canada Japan United States Canada Great B r i t a i n Japan United States Great B r i t a i n Japan United States Canada Denmark Great B r i t a i n Japan United States Denmark Great B r i t a i n Japan United States Canada Denmark Great B r i t a i n Japan United States

1973

1974

1975

1976

1977

1978

1979

1980

Number of Outbreaks

2 4 6 3 3 12 1 1 10 1 7 6 1 3 4 3 2 3 13 1 6 3 2 7 3 43 7 12 2 8 28 4 NA

Number of Cases

70 137 ?

2702 10 326 33 1 26 1 396 16 2 9 31 43 3 69 71 5 ?

9 32 30 ?

179 321 132 3 ?

77 153 NA


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misnomer. A more appropriate name for this foodborne disease would be histamine poisoning. Among the non-scombroid f i s h , mani-mani i s the most common f i s h implicated in histamine poisoning in the U.S. Other non-scombroid f i s h that have been involved in outbreaks of histamine poisoning are sardines, pilchards, anchovies, herring, black marlin, and kahawai.


Other Foods. Cheese has been implicated in several outbreaks of histamine poisoning in the U.S., Canada, France, and the Netherlands (5-8). Swiss cheese has been involved in a l l of the U.S. incidents and the French outbreak, while cheddar and Gouda cheese were involved in the Canadian and Dutch outbreaks, respectively. Ham has allegedly been involved in an outbreak in France; sauerkraut was implicated in one case in Germany (9); chicken was associated with an outbreak in Japan. Evidence that Histamine i s the Causative Agent The evidence supporting the role of histamine as the causative agent of scombroid poisoning i s rather compelling (1.10). Many incidents of scombroid poisoning have been investigated over the years and, i n most cases where samples were available for analysis, the levels of histamine were high. The symptoms of scombroid poisoning are consistent with the involvement of histamine; they mimic the symptoms observed in a l l e r g i c reactions or following intravenous histamine administration. F i n a l l y , the e f f i c a c y of antihistamines in the treatment of scombroid poisoning provides perhaps the strongest evidence for the involvement of histamine i n this disease. The results of animal and human challenge studies also support the role of histamine in scombroid poisoning to some extent. Oral administration of histamine to pigs and dogs e l i c i t s an emetic reaction (11.12). Intraduodenal injection of histamine in rats and cats produced transient hypotension (13). Intraduodenal i n j e c t i o n of a histamine containing yeast extract into cats produced a variety of histamine l i k e effects including increased volume and a c i d i t y of gastric secretion, increased hematocrit and limb volume, and enhanced electromyographic a c t i v i t y (13.)· M o t i l and Scrimshaw (14) observed some mild and transient symptoms reminiscent of scombroid poisoning in human challenge studies following o r a l administration of 100-180 mg of histamine in combination with wholesome tuna. While the evidence implicating histamine as the causative agent of scombroid poisoning i s compelling, Japanese investigators at one time isolated a histamine l i k e substance c a l l e d saurine that was possibly involved in scombroid poisoning (15.). Saurine has since been i d e n t i f i e d as the phosphate s a l t of histamine (16). The Paradox Given the compelling evidence that histamine i s the causative agent in scombroid poisoning, o r a l l y administered histamine i s remarkably non-toxic to humans (14.17.18). Weiss et a l . (17) f i r s t demonstrated the lack of t o x i c i t y of o r a l l y administered histamine



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to humans in 1932. They showed that 180 mg of histamine was without noticeable e f f e c t when administered o r a l l y while 7 ug of histamine would cause vasodilation and increases in the heart rate when given intravenously. Granerus (18) challenged human subjects o r a l l y with up to 67.5 mg of histamine and observed a similar lack of toxic response. M o t i l and Scrimshaw (14) administered 100-180 mg of histamine in combination with tuna and noted some transient toxic effects as mentioned e a r l i e r . However, the doses necessary to e l i c i t these mild symptoms were several times higher than the doses producing more severe symptoms when consumed with spoiled scombroid fish. This paradox between the lack of t o x i c i t y of pure histamine and the apparent t o x i c i t y of equivalent doses of histamine in spoiled f i s h could be explained by the existence of potentiators of histamine t o x i c i t y in spoiled f i s h . These potentiators would serve to lower the threshold dose of histamine necessary to e l i c i t scombroid poisoning symptoms in humans. Evidence for the Involvement of Potentiators of Histamine T o x i c i t y Several possible potentiators of histamine t o x i c i t y have been suggested by various in vivo and in v i t r o experiments, although none of these substances has been c l e a r l y implicated in scombroid poisoning. Miyaki and Hayashi (19) isolated an unidentified synergistic factor from dried seasoned saury. Subsequently, Hayashi (20) reported that trimethylamine, trimethylamine oxide, agmatine, and choline could potentiate the c o n t r a c t i l e effect of histamine on guinea pig uterus. This report was l a t e r disputed by Kawabata et a l . (21) who found that trimethylamine and trimethylamine oxide were i n e f f e c t i v e in promoting the action of histamine on guinea pig uterus. Mongar (22) observed that short-chain a l i p h a t i c diamines, such as cadaverine and putrescine, could competitively i n h i b i t diamine oxidase (DAO), an enzyme active in d e t o x i f i c a t i o n of histamine. These diamines could potentiate histamine-induced contractions of guinea pig ileum (22). Inhibitors of DAO, such as cadaverine, were shown to potentiate the contraction of guinea pig ileum, trachea, and uterus (23). Several iri vivo experiments in animals and humans suggest the existence of potentiators of histamine t o x i c i t y in spoiled f i s h . Parrot and Nicot (24) demonstrated that putrescine enhanced the l e t h a l i t y of o r a l l y administered histamine in guinea pigs. Cadaverine has been shown to have a similar e f f e c t on the o r a l t o x i c i t y of histamine in guinea pigs (25). Weiss et a l . (17) showed that 180 mg of histamine was without e f f e c t when administered o r a l l y to humans, while Motil and Scrimshaw (14) did observe some toxic symptoms after o r a l administration of an equivalent dose of histamine with "wholesome" tuna. Further experiments w i l l be necessary with f i s h incriminated i n histamine poisoning outbreaks to confirm the presence and identity of any potentiators of histamine t o x i c i t y .


SEAFOOD TOXINS

422 Histamine Metabolism and i t s I n h i b i t i o n

The p r i n c i p a l pathways for the biogenesis and metabolism of histamine are well known. Histamine i s formed by decarboxylation of the amino acid, L - h i s t i d i n e , a reaction catalyzed by the enzyme, h i s t i d i n e decarboxylase. This decarboxylase i s found i n both mammalian and non-mammalian species. The mammalian enzyme requires pyridoxal phosphate as a cofactor. The b a c t e r i a l enzyme has a d i f f e r e n t pH optimum and u t i l i z e s pyruvate as a cofactor (26,27). Two major histaminé-metabolizing enzymes, DAO (histaminase) and histamine N~methyltransferase (HMT) are found in mammalian tissues. The product of HMT, N -methyl-histaminé (Ν -ΜΗ), i s mostly converted by monoamine oxidase (MAO) to N -methylimidazole acetic acid (Ν -Μ1ΑΑ). In the other pathway, the product of DAO, imidazole acetic acid (IAA), can be conjugated to form imidazole acetic acid riboside (ΙΑΑ-riboside). Very l i t t l e histamine i s excreted unchanged. The r e l a t i v e importance of the two enzymatic routes varies among species (28). In man, the pathways for parenterally administered [**C]-histamine have been mapped (29). Analysis of urine samples showed that Ν -ΜΙΑΑ was the p r i n c i p a l metabolite (42-47%), with smaller quantities of IAA-riboside (16-23%), IAA (9-11%), Ν ~ΜΗ (4-8%), and unchanged histamine (2-3%). When [ C]-histamine was given o r a l l y instead of intravenously, much less r a d i o a c t i v i t y could be recovered in the urine (18). Sjaastad and Sjaastad (30) explained t h i s low recovery by a finding that part of the radioactive metabolites were excreted in the feces. They also found that some of the r a d i o a c t i v i t y was exhaled as **C02, due to metabolism of the imidazole ring in the gut. A portion of the o r a l l y administered histamine i s also converted by i n t e s t i n a l bacteria to N-acetylhistamine. HMT and DAO a c t i v i t i e s are quite high in the small i n t e s t i n a l mucosa (31), and i t i s thought that the majority of an o r a l dose of histamine i s metabolized as i t traverses the i n t e s t i n a l mucosa or as i t c i r c u l a t e s through the l i v e r (32). T

τ

T


τ

τ

τ

14

HMT Inhibitors. HMT i s very selective toward histamine. In the HMT reaction, S-adenosylmethionine serves as the methyl donor. HMT i s inhibited by S-adenosylmethionine analogues, such as S-adenosylhomocysteine (33). Other i n h i b i t o r s of HMT include antimalarial drugs, e.g. chloroquin and amodiaquin, and antihistaminic agents (34-36). Together with DAO, t h i s enzyme i s subject to substrate i n h i b i t i o n by high concentrations of histamine (37). HMT i s also inhibited by the histamine H 2 receptor agonists, dimaprit and impromidine (38.39). DAO Inhibitors. Unlike HMT, DAO i s not selective towards histamine. I t oxidizes other diamines, e.g. putrescine. Many i n h i b i t o r s of DAO have been i d e n t i f i e d ; the most well-known example is aminoguanidine. Many antihistaminic agents and related drugs are good i n h i b i t o r s of DAO (40). Other DAO i n h i b i t o r s include bases, such as amidines and guanidines, carbonyl agents, substituted hydrazines, and chelating agents (41,42). Many of these known DAO i n h i b i t o r s belong to a class of drugs c a l l e d monoamine oxidase i n h i b i t o r s (43).


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MAO Inhibitors. MAO i s an enzyme which oxidizes a variety of monoamines. Among the substrates of this enzyme are tyramine, tryptamine, 5-hydroxytryptamine, histamine, and short chain a l i p h a t i c monoamines (44)· Oxidation of histamine to imidazoleacetaldehyde can be carried out by DAO as well as MAO. MAO is also responsible for the conversion of Ν -ΜΗ, the product of HMT, to Ν -Μ1ΑΑ. Many MAO i n h i b i t o r s have been i d e n t i f i e d ; they are conventionally divided into hydrazides, hydrazines and amines (44). Some MAO i n h i b i t o r s , e.g. the hydrazines, are non-selective; they also i n h i b i t DAO. τ

τ


Potentiation v i a Enzyme I n h i b i t i o n Since the majority of an o r a l dose of histamine i s excreted as various histamine metabolites, the metabolism of histamine probably serves as a d e t o x i f i c a t i o n mechanism. As noted e a r l i e r , the small intestine and l i v e r are p a r t i c u l a r l y active in histamine metabolism and would be expected to protect against the t o x i c i t y of o r a l l y administered histamine. The hypothesis that histamine t o x i c i t y could be potentiated by i n h i b i t i o n of histamine metabolizing enzymes was supported by early experiments that demonstrated a potentiation of histamine-induced contractions of smooth muscle by i n h i b i t o r s of DAO (22.23). However, these experiments were not directed at the o r a l t o x i c i t y of histamine. Taylor and Lieber (45) showed that rat i n t e s t i n a l HMT and DAO could be inhibited in v i t r o by certain amines, including some putrefactive amines that are known to occur in spoiled f i s h (46,47). Many of these amines inhibited only one of the two histamine metabolizing enzymes, but several including cadaverine and aminoguanidine were e f f e c t i v e inhibitors of both HMT and DAO (45). Mixtures of the i n h i b i t o r s were not tested, but would be predicted to be quite e f f e c t i v e in i n h i b i t i n g i n t e s t i n a l histamine metabolism. The in v i t r o experiments of Lyons et a l . (48) provide the best evidence that potentiation operates through the i n h i b i t i o n of the histamine metabolizing enzymes. In these experiments, rat i l e a l segments were perfused i n v i t r o with either histamine alone or histamine plus an equimolar amount of cadaverine, aminoguanidine, or anserine. A tracer quantity of histaminé was added to the perfusate. The i l e a l segments were bathed in an oxygenated, nutrient medium throughout the experiment. The serosal f l u i d was sampled p e r i o d i c a l l y during a 2-h incubation, counted for t o t a l t r i t i u m , and monitored for histamine and i t s major metabolites a f t e r separation by thin-layer chromatography. The transport of r a d i o a c t i v i t y from the lumen to the serosal f l u i d was not affected by the presence of cadaverine, aminoguanidine, or anserine. However, as shown in Table I I , the r a t i o of histamine to i t s metabolites was altered substantially by the presence of cadaverine and aminoguanidine. In the presence of these substances, more unmetabolized histamine reached the serosal f l u i d indicating that i n h i b i t i o n of i n t e s t i n a l histamine metabolism had been e f f e c t i v e i n potentiating the uptake of histamine. Anserine was i n e f f e c t i v e .


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Percent of Serosal Radioactivity Represented by Histamine a f t e r 2-h I n t e s t i n a l Perfusions in the Presence or Absence of P o t e n t i a t o r s ( 4 8 J

Additions to Luminal Perfusate

1


Histamine Histamine + Cadaverine Histamine + Aminoguanidine Histamine + Anserine

a

I n i t i a l concentration of each amine in the perfusate was 5.4 mM. ^Average + SEM

% Histamine

22.9 67.0 60.4 30.6

+ + + +

1

5.9 11.9 5.1 6.4

luminal

of 4 t r i a l s .

Further research w i l l be necessary to demonstrate conclusively that i n h i b i t i o n of histamine metabolism i s responsible for the potentiation of histamine t o x i c i t y that is apparently observed i n scombroid poisoning. In vivo experiments w i l l be necessary to show that hepatic histamine metabolism i s also compromised by the ingestion of suspected potentiators. Also, the effectiveness of cadaverine and other possible potentiators must be demonstrated under conditions where the histamine l e v e l exceeds the potentiator concentration by a factor of approximately 10. This concentration r a t i o would p a r a l l e l that found in spoiled tuna more c l o s e l y than the l e v e l s used in the experiments of Lyons et a l . (48). Additional circumstantial evidence for the v a l i d i t y of the i n h i b i t i o n hypothesis of potentiator action may come from several recent outbreaks of histamine poisoning. Isoniazid, an antituberculosis agent and known i n h i b i t o r of DAO, has played a r o l e in several outbreaks of histamine poisoning (49-52). These outbreaks a l l involved patients on i s o n i a z i d therapy who developed histamine poisoning symptoms a f t e r ingestion of f i s h or cheddar cheese containing marginally toxic amounts of histamine. In these cases, i n h i b i t i o n of DAO by i s o n i a z i d may have enhanced the t o x i c i t y of these marginally toxic levels of histamine. Other Possible Mechanisms of Potentiation Another possible mechanism of potentiator action, the b a r r i e r disruption hypothesis, has received considerable attention. This theory of potentiator action, f i r s t proposed by Parrot and Nicot (?4)» suggests that the potentiators may i n t e r f e r e with the protective actions of i n t e s t i n a l mucin. Mucin i s known to bind histamine in. v i t r o (53), and Parrot and Nicot (24) suggested that this binding was e s s e n t i a l to prevent passage of histamine across the i n t e s t i n a l w a l l . Potentiators such as putrescine and cadaverine


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may bind competitively and p r e f e r e n t i a l l y with mucin f a c i l i t a t i n g the movement of histamine into the c i r c u l a t i o n (24.54). The results of the i n t e s t i n a l perfusion studies of Lyons et a l . (48) cannot be explained on the basis of the b a r r i e r disruption hypothesis. The barrier disruption hypothesis would predict an increase in the o v e r a l l transport of r a d i o a c t i v i t y in the presence of potentiators; this was not observed by Lyons et a l . (48)· The changes in the r a t i o of histamine to i t s metabolites obtained in the experiments of Lyons et a l . (48) would not be predicted by the b a r r i e r disruption hypothesis either. In support of the b a r r i e r disruption hypothesis, Jung and Bjeldanes (54) demonstrated that i n t e s t i n a l transport of r a d i o a c t i v i t y was potentiated by incubation of equimolar amounts of cadaverine and ^C-histamine £ non-everted gut sacs over a 2-h incubation period. Additionally, the r a t i o of histamine to i t s metabolites was not altered in the presence of cadaverine. These results are in d i r e c t c o n f l i c t with those obtained by Lyons et a l . (48). However, the experiments of Jung and Bjeldanes (54) appear to have been flawed. Plattner et a l . (550 showed that everted gut sacs are useful for only 30 min in oxygenated, nutrient medium before considerable c e l l membrane damage occurs. Non-everted gut sacs, as used by Jung and Bjeldanes (54) would be predicted to be less viable due to the greater lack of oxygen and nutrient exposure of the e p i t h e l i a l c e l l s of the v i l l i . Jung and Bjeldanes (54) used 3-h incubations of the non-everted gut sacs and provided no h i s t o l o g i c a l evidence of tissue i n t e g r i t y . Lyons et a l . (48) demonstrated extensive h i s t o l o g i c a l damage in non-everted gut sacs of rats a f t e r 30 min of incubation. Later, Chu and Bjeldanes (53) showed that the binding histamine to mucin could be inhibited in. v i t r o by spermine, spermidine, putrescine, cadaverine, and a basic extract of tuna. The i n h i b i t i o n required r e l a t i v e l y high amine concentrations, and the concentrated tuna extract exerted only a 23% i n h i b i t i o n of binding (53). Each mole of i n t e s t i n a l mucin can bind 2.5 moles of histamine (53). Given the vast molar excess of mucin to histamine in the g a s t r o i n t e s t i n a l t r a c t , i t i s d i f f i c u l t to envision that such i n h i b i t i o n of binding would play more than a secondary role in the potentiation of histamine t o x i c i t y .


n

PharmacoloRical-ToxicoloRical Actions of Histamine H] and Hp Receptors. Histamine exerts i t s actions by binding to receptors on c e l l membranes. Two types of histamine receptors, the Hi and H 2 receptors, are known; s p e c i f i c agonists and antagonists exist for each of these receptors. Black et a l . ( 5 5 ) d i f f e r e n t i a t e d Ηχ and H 2 receptors with the compounds, 2-methylhistaminé and 4-methylhistaminé. 2-Methylhistamine i s active on tissues with Ηχ receptors; 4-methylhistaminé i s active on tissues with H 2 receptors. C l a s s i c a l antihistaminic drugs were developed in the 1930 s; these compounds block Ηχ but not H 2 receptors. Among the c l i n i c a l l y used Ηχ-blockers are derivatives of ethanolamine, ethylenediamine, alkylamine, piperazine and phenothiazine (32). These agents are valuable in the treatment of #


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various a l l e r g i c responses, common cold, and motion sickness. Many of these agents are also used as hypnotics, and as l o c a l anesthetics to r e l i e v e pain and itching. The c l a s s i c a l antihistaminics block many but not a l l of the manifestations of a l l e r g i c reactions. This lack of complete effectiveness led to the hypothesis that a second type of histamine receptor existed. In 1972, Black et a l . (55) discovered a new series of antagonists which they c a l l e d H 2 receptor blockers. Burimamide was the f i r s t highly e f f e c t i v e H2"blocker, but i t was poorly absorbed o r a l l y . The modified compound, metiamide, had better absorption but was found to cause granulocytopenia (57.58). F i n a l l y , cimetidine was tested and found to be a potent and r e l a t i v e l y non-toxic antagonist (59). Cimetidine is now widely used c l i n i c a l l y to treat duodenal u l c e r s , Z o l l i n g e r - E l l i s o n Syndrome and other gastric hypersecretory diseases (32). Mast C e l l s and Basophils. The chief sites of histamine storage are mast c e l l s in the tissues and basophils in blood. These c e l l s synthesize histamine and store i t in secretory granules along with a heparin-protein complex. In response to s p e c i f i c antigens, mast c e l l s or basophils are s e n s i t i z e d . Histamine i s then secreted from the storage granules. Besides the histamine stores in mast c e l l s and basophils, there i s evidence of non-mast c e l l histamine i n some tissues, p a r t i c u l a r l y gastric and i n t e s t i n a l mucosa (60). PharmacoloRical-ToxicoloKical Responses to Histamine. The p r i n c i p a l pharmacological actions of histamine were outlined by Dale and Laidlaw in the 1910*s (61,62). They noted that the predominant e f f e c t s of histamine varied between species. Many of these e f f e c t s are similar to the symptoms seen in histamine poisoning outbreaks (3,10). In man, the effects of histamine on the cardiovascular system are very important. The actions on this system involve both Hi and H 2 receptors. Histamine causes d i l a t a t i o n of small blood vessels and c a p i l l a r i e s , and c o n s t r i c t i o n of larger blood vessels (63). The symptoms of flushing and headache experienced by many of the victims are caused by the d i l a t i n g action of histamine on small blood vessels, c a p i l l a r i e s , and venules. Another c l a s s i c a l e f f e c t of histamine on small blood vessels i s the increased permeability (32). This i s responsible for the u r t i c a r i a (hives) seen in many outbreak cases. In a small percentage of victims, cardiac p a l p i t a t i o n was reported (9), which results from the d i r e c t e f f e c t s of histamine on the heart. Histamine increases both the c o n t r a c t i l i t y and the pacemaker rate of the heart (32.). In very severe cases, histamine shock can occur (10) due to a profound f a l l in blood pressure, but this requires large doses of histamine (32). Histamine also acts on extravascular smooth muscles to cause contraction or relaxation. Most often, contraction i s due to activation of H^ receptors and relaxation to a c t i v a t i o n of H 2 receptors (32). In man, histamine causes contraction of bronchial and i n t e s t i n a l smooth muscles. Histamine-induced contraction of guinea pig ileum i s a standard bioassay for histamine. Its e f f e c t s on smooth muscle of the eye and genitourinary tract are important i n some species but not in human (64.). In scombroid poisoning cases,



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most of the victims experienced g a s t r o i n t e s t i n a l symptoms, i . e . abdominal cramps, diarrhea, nausea, and vomiting (34.)· I t i s known that contraction of i n t e s t i n a l smooth muscle leads to cramps and diarrhea (64). However, the mechanism that leads to nausea and vomiting i s not c l e a r l y understood. Histamine also evokes a copious secretion of highly acidic gastric juice from the gastric glands at doses below those that influence blood pressure (32). This e f f e c t of histamine i s mediated through H 2 receptors on the p a r i e t a l c e l l s . The importance of this effect i n scombroid poisoning i s not known. Histamine also has some stimulant actions on salivary, pancreatic, i n t e s t i n a l , bronchial, and lacrimal secretions (32), but these effects are r e l a t i v e l y unimportant. Histamine i s a powerful stimulant of nerve endings, both motor and sensory nerves (32). Its stimulation i s important in producing pain and itching, which are important components of the u r t i c a r i a l response and reactions to insect stings (64). This effect i s mediated through Ηχ receptors. Such nerve stimulation might conceivably be important in the i n i t i a t i o n of the emetic response. Threshold Toxic Dose for Histamine i n Foods and Regulatory Limits The threshold toxic dose for histamine i n foods i s not precisely known. Estimates are d i f f i c u l t to acquire from outbreaks of histamine poisoning because of the v a r i a b i l i t y i n histamine content in the f i s h (1,65). Simidu and H i b i k i (66) estimated the threshold toxic dose for histamine i n f i s h to be approximately 60 mg/100 g, but their methods were not t e r r i b l y precise. Based on experience acquired i n the investigation of hundreds of scombroid poisoning incidents, the U.S. Food and Drug Administration recently established 50 mg/100 g as the hazard action l e v e l for histamine i n tuna. They have not yet established regulatory l i m i t s for histamine in other f i s h or cheese. The existence of potentiators could dramatically influence the threshold toxic dose for histamine i n foods. Since d i f f e r e n t f i s h might be expected to vary i n the type and amount of the various potentiators, the threshold toxic dose for histamine would be expected to vary from f i s h to f i s h also. The differences i n type and amount of the potentiators would be predicted from expected differences i n the types of microflora, the metabolic c a p a b i l i t i e s of the microflora, and conditions of spoilage. Even greater differences would be expected i n the comparisons of d i f f e r e n t species of f i s h or in comparisons of f i s h and cheese. Consequently, although the health hazard associated with ingestion of tuna containing 50 mg histamine per 100 g i s established, the hazard associated with 50 mg histamine/100 g i n other f i s h and cheese remains to be determined. U n t i l the role of the potentiators can be more completely elucidated, i t may be premature to establish regulatory l i m i t s f o r histamine i n f i s h or other foods on the basis of health hazards.



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Toxicology of Scombroid Poisoning - ACS Publications - American

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