Toxicants Occurring Naturally in Foods. (1966)

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54 IRWIN B. LIENER Feeding experiments with purified preparations of the hemagglutinins clearly implicate these substances as being responsible, at least in part, for the toxicity of certain legumes. Liener5! reported that hemagglutinin comprising | percent of a diet containing heated soybean meal caused a significant depression of the growth of rats. It was estimated that the soybean hemagglutinin accounted for about one half of the growth inhibition that is obtained when raw soybeans replace the heated soybeans in such diets. Jaffé52 and Honavar et al.45 have also shown that the purified hemagglutinins of the black bean (Phaseolus vulgaris) can markedly inhibit the growth of rats at levels as low as 0.5 percent of the diet. Death accompanied growth depression when levels of the black bean hemagglutinin exceeded 1 percent of the diet. The hemag- glutinin isolated from the kidney bean (Phaseolus vulgaris) was some- what more toxic, causing death and depressed growth at a level of 0.5 percent of the diet.45 Wagh et al. have shown that the kidney bean hemagglutinin also inhibits the growth of chicks without producing pancreatic hypertrophy. Pancreatic enlargement is known to accompany the ingestion of raw soybeans and is attributed to the effects of a trypsin inhibitor.*4 Experiments by Jaffé and co-workers®25556 provide a possible ex- planation for the deleterious effects of the orally ingested hemaggluti- nins, Digestibility measurements made on rats fed the black bean hemagglutinin (phaseolotoxin A) revealed a sharp diminution in the absorption of protein and fat. A 50 percent decrease in the absorption of glucose was observed in perfusion experiments with intestinal loops taken from rats fed phaseolotoxin A. Jaffé believes that the action of the hemagglutinin is to combine with the cells lining the intestinal wall (in much the same fashion as it combines with red blood cells), thus causing a nonspecific interference with the intestinal absorption of all nutrients. DeMuelenaere*’ has recently reported that a crude prepara- tion of the soybean trypsin inhibitor likewise led to an impairment in the absorption of amino acids through the intestinal wall. This effect may have been due to the hemagglutinin content of the trypsin in- hibitor fraction used in this study since crude trypsin inhibitor prepara- tions are known to contain appreciable amounts of the hemagglutinin.'6 REFERENCES 1. I.E. Liener, “Seed Hemagglutinins,” Econ. Botany, 18, 27 (1964). 2. O. Wienhaus, “Zur Biochemie des Phasins,” Biochem. Z., 18, 228 (1909).

HEMAGGLUTININS 55 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 21. 23. 24. 25. K. Landsteiner and H. Raubitschek, ‘“‘Beobachtungen iiber Hamolyse und Hamagglutination,” Zentr. Bakteriol., 45, 660 (1907). V. R. Goddard and L. B. Mendel, “Plant Hemagglutinins with Special Reference to a Preparation from the Navy Bean,” J. Biol. Chem., 82, 447 (1929). L. B. Mendel, “Vegetable Agglutinins,”’ J. Biol. Chem., 6, XTX (1909). E. C. Schneider, “The Hemagglutinating and Precipitating Properties of the Bean (Phaseolus),”’ J. Biol. Chem., 11, 47 (1911). K. Fujiwara, “Isolierungversuche mit Soja-agglutinin und Anti-agglutinin,” Biochem. Z., 140, 113 (1923). W. C. Boyd and E. Shapleigh, “Specific Precipitating Activity of Plant Agglutinins (Lectins),” Science, 119, 419 (1954). W. C. Boyd, D. M. Green, D. M. Fujinaga, J. S. Drabik, and E. Waszczenko- Zacharczenko, “‘A Blood Factor, Possibly New, Detected by Extracts of Arachis hypogaea,” Vox Sanguinas, 4, 456 (1959). J. B. Sumner and S. F. Howell, ‘“‘Non-identity of Jack Bean Agglutinin with Crystalline Urease,”’ J. Immunol., 29, 133 (1935). L. B. Sumner, S. F. Howell, and A. Zeissig, ‘“‘Concanavalin A and Hemag- glutination,” Science, 82, 65 (1935). J. B. Sumner and S. F. Howell, “The Identification of the Hemagglutinin of the Jack Bean with Concanavalin A,” J. Bacteriol., 32, 227 (1936). H. A. de Souza, ‘“‘Hemagglutinins in Legumes,” Rey. Brasil. Farm., 30, 189 (1948). W. G. Jaffé, “Protein Digestibility and Trypsin Inhibitor Activity of Legume Seeds,”’ Proc. Soc. Exptl. Biol. Med., 75, 219 (1950). G. W. G. Bird, “Specific Agglutinating Activity for Human Red Blood Cor- puscles in Extracts of Dolichos biflorus,’’ Current Sci. (India), 20, 298 (1951). I. E. Liener, “The Intraperitoneal Toxicity of Concentrates of the Soy Bean Trypsin Inhibitor,” J. Biol. Chem., 193, 183 (1951). W. C. Boyd and R. M. Reguera, ‘“‘Hemagglutinating Substances for Human Cells in Various Plants,” J. Immunol., 62, 333 (1949). M. Kriipe, ‘‘Hamagglutinine mit spezifischen Affinitaten in Samen von Papilio- naceen,”’ Biol. Zentr., 72, 424 (1953). G. W.G. Bird, “*A Further Serological Distinction between the Haemagglutinins of Dolichos biflorus and Phaseolus lunatus,” Nature, 174, 1015 (1954). W. C. Boyd, E. Shapleigh, and M. McMaster, “Immunochemical Behavior of a Plant Agglutinin (Lectin),” Arch. Biochem. Biophys., 55, 226 (1955). K. F. Schertz, W. Jurgelsky, Jr., and W. C. Boyd, “Inheritance of Anti-A Hemagglutinating Activity in Lima Beans, Phaseolus lunatus,” Proc. Natl. Acad. Sci. U.S., 46, 529 (1960). D. A. Rigas and E. E. Osgood, “Purification and Properties of the Phytohe- magglutinin of Phaseolus vulgaris,” J. Biol. Chem., 212, 607 (1955). M. Saint-Paul, F. Daoules-LeBourdelles, and J. M. Fine, “‘Biochemical Study of the Hemagglutinin of Phaseolus vulgaris,”” Compt. Rend. Soc. Biol., 150, 1742 (1956). W. G. Jaffé and K. Gaede, “Purification of a Toxic Phytohemagglutinin from Black Beans (Phaseolus vulgaris),”” Nature, 183, 1329 (1959). M. Coulet, M. J. Bezou, and B. Cognet, “Separation and Properties of the Agglutinant Principle of the Seeds of Phaseolus vulgaris L.,”” Bull. Soc. Chim. Biol., 41, 1385 (1959).

36 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 39. 41. 42. 43. 45. IRWIN E. LIENER M. Kunitz and M. R. McDonald, “Isolation of Crystalline Ricin,” J. Gen. Physiol., 32, 25 (1948). W. B. Creger and W. Gifford, ‘“‘Some Interrelationships of Blood and the Fava Bean Principle in vitro,” Blood, 7,721 (1952). E. Cugudda, C. Gigli, and S. Massenti, “Pathogenesis of Favus. Hemagglutina- tion and Hemolytic Activity of Some Chemical Constituents,” Minerva Med., 44, I, 140 (1953). U. Carcassi, ‘“‘“Hemagglutinating Power of Broad Bean Extracts. Demonstra- tion of Transfer of the Agglutinating Substance from Erythrocyte,” Minerva Med., 44, I, 1152 (1953). F. Ottensooser, “On Hemagglutinins of Vicia Species,” Anais. Acad. Brasil. Cien., 27, 519 (1955). E. A. Kabat, M. Heidelberger, and A. E. Bezer, ““A Study of the Purification and Properties of Ricin,” J. Biol. Chem., 168, 629 (1947). T. Takahashi, G. Funatsu, and M. Funatsu, ‘‘Biochemical Studies on Castor Bean Hemagglutinin. II. Hemagglutinin Separated from Crystalline Ricin and Its Molecular Weight,” J. Biochem. (Japan), 52, 50 (1962). J. B. Sumner, N. Gralen, and I.-B. Eriksson-Quensel, ‘““The Molecular Weights of Canavalin, Concanavalin A, and Concanavalin B,” J. Biol. Chem., 125, 45 (1938). M. J. Pallansch and I. E. Liener, “‘Soyin, A Toxic Protein from the Soybean. II. Physical Characterization,” Arch. Biochem. Biophys., 45, 366 (1953). S. Wada, M. J. Pallansch, and I. E. Liener, ‘Chemical Composition and End- groups of the Soybean Hemagglutinin,” J. Biol. Chem., 233, 395 (1958). W. G. Jaffé, “‘Fucose, Xylose, and Galactose Identified in a Glycoprotein Obtained from Black Kidney Beans (Phaseolus vulgaris), Acta Cient. Venezolana, 13, 100 (1962). I. E. Liener and J. E. Rose, ““Soyin, A Toxic Protein from Soybean. ITI. Immuno- chemical Properties,” Proc. Soc. Exptl. Biol. Med., 83, 539 (1953). T. B. Osborne, L. B. Mendel, and I. F. Harris, ‘‘A Study of the Proteins of the Castor Bean with Special Reference to the Isolation of Ricin,” Am. J. Physiol., 14, 259 (1905). R. Borchers, “Castor Bean Oil Meal. I. Destruction of the Toxic Factor,” Poultry Sci., 28, 568 (1949). . R. Kodras, C. K. Whitehair, and R. MacVicar, “Studies on the Detoxication of Castor Seed Pomace,”’ J. Am. Oil Chemists’ Soc., 26, 641 (1949). D. B. Jones, “‘Proteins of the Castor Bean—Their Preparation, Properties, and Utilization,” J. Am. Oil Chemists’ Soc., 24, 247 (1947). F. B. Jenkins, “‘Allergenic and Toxic Components of Castor Bean Meal: Review of the Literature and Studies of the Inactivation of These Components,” J. Sci. Food Agr., 14, 773 (1963). I. E. Liener, in Processed Plant Protein Foodstuffs, A. M. Altschul, ed., Academic Press, New York (1958), Chap. 5. I. E. Liener, “Toxic Factois in Edible Legumes and Their Elimination,” Ayn. J. Clin. Nutr., 11, 281 (1962). P. M. Honavar, C. V. Shih, and I. E. Liener, “The Inhibition of the Growth of Rats by Purified Hemagglutinin Fractions Isolated from Phaseolus vulgaris,” J. Nutr., 77, 109 (1962). W. G. Jaffé, “Toxicity of Raw Kidney Beans,” Experientia, 5,81 (1949).

HEMAGGLUTININS 57 47. 48. 49. 50. Sl. 32. 53. 55. 56. 37. W. G. Jaffé, “Limiting Essential Amino Acids of Some Legume Seeds,” Proc. Soc. Exptl. Biol. Med., 71, 398 (1949). HI. Faschingbauer and L. Kofler, “Uber Giftwirkung von rohen Bohnen und Bohnenkeimlingen,” Wien. Klin. Wochschr., 42, 1069 (1929). C. Griebel, “Erkrankungen durch Bohnenflochen (Phaseolus vulgaris L.) und Platterbsen (Lathyrus tingitanus L.),”” Z. Lebensm.-Untersuch.-Forsch., 90, 191 (1950). G. E. Cartwright and M. M. Wintrobe, “‘Hematologic Survey of Repatriated American Military Personnel,” J. Lab. Clin. Med., 31, 886 (1946). I. E. Liener, “‘Soyin, A Toxic Protein from the Soybean. I. Inhibition of Rat Growth,” J. Nutr., 49, 527 (1953). W. G. Jaffé, “Uber Phytotoxine aus Bohnen (Phaseolus vulgaris), Arzneimittel- Forsch., 10, 1012 (1960). P. V. Wagh, D. F. Klaustermeier, P. E. Waibel, and I. E. Liener, “Nutritive Value of Red Kidney Beans (Phaseolus vulgaris) for Chicks,” J. Nutr., 80, 191 (1963). S. S. Chernick, S. Lepkovsky, and I. L. Chaikoff,““A Dietary Factor Regulating the Enzyme Content of the Pancreas. Changes Induced in Size and Proteolytic Activity of the Chick Pancreas by the Ingestion of Raw Soy-Bean Meal,” Am. J. Physiol., 155, 33 (1948). W. G. Jaffé and G. Camejo, “‘La accion de una proteina toxica, aislada de caraotas negras (Phaseolus vulgaris) sobre la absorcion intestinal en ratas,” Acta Cient. Venezolana, 12, 59 (1961). W. G. Jaffé, A. Planchart, J. I. Paez Pumar, R. Torrealba, and D. Nully Franceschi, ““A Toxic Factor in Raw Beans (Phaseolus vulgaris),”’ Arch. Venezolana Nutr., 6, 195 (1955). H, J. H. de Muelenaere, “Studies on the Digestion of Soybeans,” J. Nutr., 82, 197 (1964).

IRWIN E. LIENER Cyanogenetic Glycosides Complex glycosides that yield hydrocyanic acid upon hydrolysis are widely distributed in the plant kingdom (Table 1). Amygdalin, first isolated from the seeds of the bitter almond, is probably the best known of these so-called cyanogenetic glycosides. Its structure, shown in Figure 1, serves to illustrate the general chemical constitution of this group of substances and the nature of their hydrolysis products. The toxicity of the cyanogenetic glycosides is directly attributable to the liberation of hydrogen cyanide (HCN) which is effected by mild acid hydrolysis or through the action of enzymes that are nearly always contained in the same plant. The term “‘emulsin”’ was originally used to designate the principle in almonds responsible for the complete hy- drolysis of cyanogenetic glycosides. It is now believed that emulsin is a mixture of enzymes in which the @-glucosidase and oxynitrilase com- ponents play dominant roles in releasing free HCN! 2 (see Figure 1). Many forage plants, notably sorghum, are known to be poisonous to animals under certain conditions, and extensive studies have been made on the amount of HCN that can be released from many varieties of sorghum grown under different environmental conditions. As pointed out, however, by Couch and Briese,‘ it is the activity of the HCN- liberating enzymes in the plant that determines the toxicity of the plant. Unless the enzyme is sufficiently active to evolve a toxic quantity of HCN quickly, the poisoning of livestock is not likely to occur. For this reason, the analysis of plants for cyanogenetic glycosides poses special problems relating not only to the total content of these substances but also to the enzymic activity that accompanies them and is responsible for the release of HCN.4-6 58

GLYCOSIDES 59 TABLE 1 The Distribution and Composition of Cyanogenetic Glycosides* NAME SOURCE HYDROLYSIS PRODUCTS Amygdalin Almonds and stone Gentiobiose + HCN + Benzaldehyde fruit kernels Prunasin Wild cherry bark D-Glucose -++ HCN + Benzaldehyde Sambrinigrin Elder bark D-Glucose -+ HCN -+- Benzaldehyde Prulaurasin Cherry laurel D-Glucose + HCN + Benzaldehyde Vicianin Vetch seeds (Vicia Vicianose -+ HCN + Benzaldehyde angustifolia) Phaseolunatin Lima bean (Phaseolus pb-Glucose -++ HCN + Acetone lunatus) Lotusin Lotus arabicus pD-Glucose -++ HCN + Lotoflavin Dhurrin Sorghum and millet | p-Glucose -++ HCN + p-Hydroxybenzal- dehyde ¢ Taken from reference 1, p. 854. Among the cyanogenetic plant foods consumed by man, the lima bean (Phaseolus lunatus) has received the most study. This legume contains the cyanogenetic glycoside, phaseolunatin, which on hydrolysis yields glucose, acetone, and HCN.’ This legume also contains the enzymes that liberate the HCN from this glycoside only if the bean is crushed prior to cooking.5* In a study of a large number of edible lima beans, Viehoever? found that the amount of HCN that could be liberated from crushed beans varied from 0.01 to 0.3 percent. Bertrand!® isolated a cyanogenetic glycoside, which he called vicianin, from the vetch, Vicia sativa var. angustifolia. Vicianin is of interest because it contains the unusual disaccharide, vicianose, composed of glucose and arabinose.! Anderson et al.,!! however, found vicianin to be nontoxic when in- jected into rats at a level of 1 mg/g of body weight. Other legumes re- ported to contain uncharacterized cyanogenetic glycosides include the Bengal gram (Cicer arietinum)'2 and the fava beans (Vicia faba).'3 Jaffé!4 determined the amount of HCN released from a wide selection of edible legumes, but found the levels of HCN (0.7 to 3.2 mg/100 g) to be insufficient to explain the poor nutritive value that many of these legumes are known to have in the unheated state. Since the liberation of HCN from its glycoside precursors is an enzymatic reaction, heat treatment would be expected to render plants containing them relatively nontoxic. Nevertheless, serious outbreaks of poisoning from cooked lima beans have been known to occur in

60 IRWIN BE. LIENER amygdalin |v O—CHo 0 CN H OH | + HC — HO\OH H/q OH H H gentiobiose mandelonitrile \e 1 benzaldehyde FicureE 1 Structure and hydrolysis products of amygdalin, a typical cyanogenetic glycoside. various parts of the world.!5-16 Gabel and Kriiger'? report an experiment in which lima beans of high HCN content, which had been boiled for 2.5 hours to inactivate the glycosidase activity, produced vomiting in human subjects; also, cyanide could be detected in the urine. These experiments raise the possibility that the body itself may contain enzymes capable of releasing HCN from phaseolunatin. Winkler,® however, found very little HCN to be released from cooked lima beans by human gastric juice, although fecal extracts and Escherichia coli did effect the release of significant amounts of HCN. It is conceivable, therefore, that the toxic effects of cyanogenetic glycosides in humans may arise from the absorption of HCN liberated in the colon through the action of bacterial enzymes.

GLYCOSIDES 61 REFERENCES 1. 2. 3. 10. 11. 12. 13. 14. 15. 16. 17. G. M. Dyson, A Manual of Organic Chemistry, Vol. I, Longmans, Green and Co., London (1950), p. 854. W. Pitman, ed., The Carbohydrates. Chemistry, Biochemistry, and Physiology, Academic Press, New York (1957), pp. 551, 563. J. F. Couch, R. R. Briese, and J. H. Martin, ““Hydrocyanic Acid Content of Sorghum Varieties,” J. Wash. Acad. Sci., 29, 146 (1939). J. F. Couch and R. R. Briese, ‘““Cyanogenesis and Enzyme Activity in Sorghum Varieties,” J. Wash. Acad. Sci., 30, 413 (1940). W. O. Winkler, “Report on Hydrocyanic Glucosides,” J. Assoc. Offic. Agr. Chemists, 34, 541 (1951). W. O. Winkler, ‘Study of Methods for Glucosidal HCN in Lima Beans,” J. Assoc. Offic. Agr. Chemists, 41, 282 (1958). W. R. Dunstan and T. A. Henry, ““Cyanogenesis in Plants. ITI. On Phaseoluna- tin, The Cyanogenetic Glucoside of Phaseolus lunatus,” Proc. Roy. Soc. (London) Ser. B, 72, 285 (1903). . J. Charlton, ‘*The Selection of Burma Beans (Phaseolus lunatus) for Low Prussic Acid Content,” Mem. Dept. Agr. India, 9, 1 (1926). A. Viehoever, “Edible and Poisonous Beans of the Lima Type (Phaseolus lunatus L.),” Thai Sci. Bull., 2, 1 (1940); cited in Chem. Abstr., 34, 67249 (1940). G. Bertrand, “La vicianine, nouveau glucoside cyanhydrique contenu dans les graines de vesce,”” Compt. Rend., 143, 832 (1906). . L. A. P. Anderson, A. Howard, and J. L. Simonsen, “Studies on Lathyrism,” Indian J. Med. Res., 12, 613 (1925). Report of the FAO/CCTA Technical Meeting on Legumes in Agriculture and Human Nutrition in Africa, Bukavu, Belgian Congo, Nov. 10-15, 1958, Food and Agriculture Organization of the United Nations, Rome, Italy (1959), p. 55. E. Cugudda, C. Gigli, and S. Massenti, “Pathogenesis of Favus. Hemagglutina- tion and Hemolytic Activity of Some Chemical Constituents,” Minerva Med., 44, I, 140 (1953). W. G. Jaffé, “‘Estudio sobre la inhibicion del crecimiento de ratas causada par Algunas semillas de Leguminosas,”” Acta Cient. Venezolana, 1, 62 (1950). W. P. Dunbar, “Rangoon Mondbohnen (Phaseolus lunatus),”” Gesundh. Ingr., 43, 97 (1920). E. Rathenasinkam, “Poisoning by Cyanogenetic Glucosides,” J, Proc. Inst. Chemists (India), 19, 59 (1947). W. Gabel and W. Kuiiger, “‘Uber die Giftwirkungen der Rangoon Bohnen,” Muench. Med. Wochsch., 67, 214 (1920).

FRANK R. BLOOD and GUILFORD G. RUDOLPH Some Naturally Occurring Stimulants and Depressants Nature has produced in the plant kingdom materials that cause many effects on the animal organism. Those materials that act on the central nervous system have proved of interest to man throughout history. Although some of these compounds produce a feeling of well-being, many can cause serious damage to the body. Compounds causing varying degrees of stimulation or depression are found in plants, many of which may be common to the garden or to the woodlands. Usually these toxicants are ingested because of ignorance of their effects, but there is a growing interest in plants containing hallucinogenic com- pounds for purposeful consumption. ‘The search for a readily available, legal, hallucinogenic material has led some individuals to the use of an old-fashioned asthma remedy containing stramonium and belladonna.! STIMULANTS Since Jimson weed contains hallucinogenic alkaloids, there have de- veloped among the “‘beatniks” Jimson weed eaters who explore the psychopharmacology of drugs in the interest of finding new sensations. Poisoning has resulted from their exploits and many cases have been reported to Poison Control Centers.2 In 1935, Jennings? reviewed the literature on stramonium poisoning and reported interesting data concerning the origin of the name Jimson weed. The Datura stramonium plant has been known by a number of names such as Jamestown weed, stink weed, thornapple, and devil’s apple.‘ The first cases of stramonium poisoning in the United States 62 th Nn A u m >» i w e t e e i e l i e e h ee Ke en e le se n ». Ms . _ me me a la l e l ll l l

STIMULANTS AND DEPRESSANTS 63 were reported by Beverly in his History and Present State of Virginia5 It was stated that in 1676 the plant was gathered for boiled salad by the soldiers during the Bacon rebellion. Some were reported to have eaten plentifully of the salad and turned into natural fools performing many simple tricks, but they remembered nothing of the incident after recovering from the effects of Jimson weed. Symptoms described for Jimson weed poisoning are “hot as a hare,”’ “blind as a bat,” “dry as a bone,” “‘red as a beet,” and “‘mad as a wet hen.’ Accidental intoxica- tion from the plant is not uncommon in the rural areas particularly in the eastern half of the United States. The leaf is used frequently in home medicines as a tea and accounts for many cases of poisoning. It is estimated that 4 to 5 g of crude leaf or seed are fatal. Children tend to be interested in tasting the fruit and are poisoned.” One report states that 100 seeds produced death in a 2-year-old child.’ Grafting of tomato plants to the roots of Jimson weed is an old custom in certain areas of the South. This technique is designed to produce larger and frost-resistant tomatoes, but cases of poisoning have been reported when the tomato plant was grafted on an above- ground secondary branch of the poisonous weed. In some primitive societies, the plants from which the major hallu- cinogens are derived have been known for many years and have been utilized for religious, medical, and social purposes including such mundane functions as allaying hunger and relieving discomfort or boredom. Among the Aztecs there were professional diviners who achieved inspiration by eating materials such as peyote. The pharma- cologist, Lewin, found mescaline, present in peyote, in wide use as an intoxicant to produce ecstatic states for special religious occasions among American Indian tribes. He identified the mescal buttons chewed by the Indians as parts of a cactus plant. The “prophetic” quality of peyote, native name of the prepared cactus, was probably known to Aztec medicine before the conquest of Cortez. What was originally a pagan rite was incorporated into the Christian liturgy of Indian groups. The mescal buttons are still chewed and the ecstatic and hallucinatory experiences are interpreted according to Christian ideas.9 Lobelius, in 1576, recorded a case of nutmeg poisoning, and, in 1832, Purkinje self-administered three nutmegs and produced a narcosis that progressed to stupor. In 1903, Wallace reported 25 cases in the world literature.!° There is some inconsistency in the amount of nutmeg re- ported to be poisonous. Green!! concluded that 5 g or more of nutmeg caused poisoning and that the toxic substance was myristicin, a con- stituent of the volatile oil. Signs and symptoms of nutmeg poisoning

64 FRANK R. BLOOD AND GUILFORD G. RUDOLPH include burning abdominal pain, delerium later alternating with stupor, low blood pressure, shock, and acidosis. A study of ten inmates of a state prison demonstrated that powdered nutmeg produced narcotic and intoxicating symptoms followed by euphoria which ended in 24 hours.!2 Also, other effects including nausea, vomiting, tachycardia, constipa- tion, drowsiness, and insomnia were reported. Nutmeg is the seed of Mpyristica fragrans. Relatively pure myristicin (90 percent) has been prepared by vacuum fractional distillation of the East Indian nutmeg oil. In 400-mg doses myristicin produced mild cerebral stimulation in human subjects. When 10 g of nutmeg that had all of its volatile constit- uents removed was ingested, tachycardia, hyperthermia, constricted pupils, and emotional lability were not produced, but some of the un- desirable effects, such as heavy sleep, persisted.!3 There is evidence for monoamine oxidase inhibition by nutmeg and its active component, myristicin, since the convulsive dose of intravenous tryptamine in mice is decreased and rat brain 5-hydroxytryptamine concentration is increased after ingestion of nutmeg or myristicin. A preliminary trial in man, in which one depressed and four schizophrenic patients were given three 500-mg capsules of ground nutmeg daily for 3 weeks, demon- strated marked improvement in one patient with some improvement in three but no response in one.!4 In 1965, two cases were reported from Sweden in which a 17-year-old girl consumed 25 g of nutmeg and a 20- year-old woman consumed 15 g of nutmeg. After a few hours both described dreamlike feelings with impaired visual perception. They re- ported experiencing music intensely. The girl slept continuously for 40 hours and awoke in a euphoric state. Symptoms lasted 10 days, whereas they usually disappear after 2 or 3 days. The authors reported that there is little likelihood of development of addiction to nutmeg.!5 The term ‘‘Coco de Mono”’ is used in Venezuela to identify various species of the genus Lecythis. In a patient ingesting 70 to 80 Coco de Mono almonds, nervousness and anxiety, violent chills, diarrhea, and anorexia were followed 8 days later by extensive loss of scalp and body hair. The almonds are said to have an agreeable taste. Experiments with mice confirmed the results seen in man, but the toxic mechanism has not been elucidated. Often the term “monkey pod” is applied to the Lecythis trees because the fruit forms in a large wooden ball with a circular opening on the bottom. The monkey reaches through the hole, grabs the nut, and cannot retract his loaded paw but allows him- self to be caught rather than release the grip.'6 Another toxic product from nuts has been reported by Moody and Moody. The Wapisiana tribe of the interior of British Guiana is re-

STIMULANTS AND DEPRESSANTS 65 ported to use whatever natural resources are available to cure the sick and to liquidate undesirable elements in the tribe. High on their list of all-purpose materials is the groundnut, Arachis hypogaea, which has been used to induce blood clotting, initiate parturition, and produce abortion. On the other hand, an extract prepared from crushed ground- nuts is said to induce insanity and finally kill the victim."” __ White snakeroot contains a compound tremetol, an unsaturated alcohol known to occur in only two plants, Eupatorium urticaefolium (E. rugosum) and Aplopappus (Haplopappus) heterophyllus. Symptoms following ingestion are anorexia, weakness, vomiting, constipation, ketosis, and, finally, coma. It was reported that Abraham Lincoln's mother died when he was 9 years old from consuming milk from a cow that had eaten white snakeroot.!® Several outbreaks of honey poisoning have occurred in New Zealand and have been attributed mainly to the presence of mellitoxin. The latter is the toxic principle of the tutu plant, Coriaria arborea.!9 Cremer and Riedmans have studied ten types of honey and identified fifty ma- terials. Over half of the materials were alcohols varying from ethanol to pentanols with many of the corresponding aldehydes present.2° American water hemlock, Cicuta maculata, is one of the most deadly wild plants in the United States.?! It is a frequent and common cause of poisoning in children who mistake it for Jerusalem artichoke. Eating this plant causes violent convulsions and unconsciousness with death, unless proper treatment is given. A number of names have been given this plant including cowbane, poison parsnip, snakeroot, snake weed, and wild carrot. The toxic agent of Cicuta maculata is known as cicutoxin, and the toxic principle from an extract of C. virosa has been crystallized and characterized as a highly unsaturated higher alcohol. Kingsbury. has described a number of other plants that produce stimulation of the central nervous system. Tobacco, when consumed, produces symptoms that include shaking, shivering, or localized twitching of muscles with staggering, weakness, and eventually pros- tration. The causative agent is the alkaloid, nicotine, present in most species of tobacco. It was reported in the Los Angeles Times, June 10, 1962, that a family was severely poisoned and one fatality resulted through the use of wild tobacco as a boiled green.”4 Persons eating bread contaminated with the seeds of the sneezeweed, Helenium tenuifolium, have been poisoned. In some cases, the poisonous principle is assumed to be dugaldin. Symptoms of poisoning in cattle include labored breathing and convulsions followed by death. The mature plant appears to be more toxic than the seedling.45

66 FRANK R. BLOOD AND GUILFORD G. RUDOLPH Goldenchain or laburnum contains the toxic quinolizidine alkaloid, cytisine, which has an action similar to nicotine. Loss of human life has occurred due to consumption of the seeds of this plant. Symptoms are excitement, incoordination, convulsions, coma, and death through asphyxiation. Dilatation of the pupils may be observed. Since cytisine is excreted in the milk, it is possible for persons using milk from poisoned animals to show its toxic symptoms.6 Black henbane or henbane, which was introduced into this hemi- sphere as a cultivated medicinal plant, has naturalized in localities such as southern Canada and the northern United States. Henbane contains alkaloids of the tropane configuration, particularly hyoscyamine, but also scopolamine. Frequent poisoning in children has been recorded.27 There are about 100 species of the genus Aconitum, which is closely related to Delphinium. Several species are cultivated as garden perennials and many grow wild in various parts of the United States. Loss of human life has occurred from ingestion of the plant or extracts made from it. Poisoning in animals and man is intense with death occur- ring in a few hours. Symptoms include restlessness, salivation, weak- ness, and irregularity of heartbeats with prostration. Aconite root may be mistaken for other edible fleshy roots.28 The xanthines (caffeine, theophylline, and theobromine) occur in plants widely distributed throughout the world. Man has made bev- erages from aqueous extracts of these plants for many years. The three best known are coffee beans which contain caffeine, tea leaves which contain caffeine and theophylline, and cocoa seeds which contain caffeine and theobromine. Some of the cola-type drinks popular in the United States contain caffeine since they are made from extracts of kola nuts which contain about 2 percent caffeine. A 6-ounce bottle of the common cola drinks has about one third the content of caffeine found in a cup of coffee.?9 Legend credits the discovery of coffee to a “‘prior of an Arabian convent.”’ Shepherds reported that goats that had eaten the berries from the coffee plant gamboled and frisked about all night instead of sleeping. The prior, mindful of the long nights of prayer he had to endure, instructed the shepherds to pick the berries so that he could make a beverage from them.3° Modern pharmacological studies of caffeine have amply confirmed the ancient beliefs and high regard for the stimulant action of this alkaloid and its derivatives. This is further exemplified by the derivation of names for the natural products, theobromine and theophylline, which mean “‘the divine food” and ‘“‘the divine leaf,” respectively.3! Caffeine in the form of its beverages tends

STIMULANTS AND DEPRESSANTS 67 to facilitate mental and muscular effort and diminishes drowsiness and psychic and motor fatigue. Theophylline is less powerful and theo- bromine virtually inactive as a central nervous system stimulant.3° The Chinese used tea as a beverage for many years before its actual description in a Chinese dictionary about 350 a.p. The poet William Cowper spoke of “‘the cups that cheer but not inebriate”’ to illustrate the distinction between the action of xanthines and alcohol.3! In man, the fatal oral dose of caffeine is estimated to be about 10 g, but no deaths have been reported. Reactions observed following the ingestion of | g or more of caffeine include insomnia, restlessness, and excitement that may progress to mild delirium. The muscles become tense and tremulous. Tachycardia and extra systoles are frequent, and respiration is quickened. The central symptoms of caffeine poisoning can be readily controlled through administration of depressants such as the short-acting barbiturates.3° Theophylline can be quite toxic and has occasionally proved fatal. Four fatalities have been reported in children treated for asthma with aminophylline (theophylline ethylenediamine).32 DEPRESSANTS Various levels of central nervous system excitability are represented by a continuum between coma and convulsions. Decreases in excitability, which vary from the normal to sedation through hypnosis, anesthesia, and finally to coma, may be brought about by depressants. The fruits and berries of some plants in nature exert a depressant effect on mam- mals when ingested. Berries from the coyotillo plant, Karwinskia humboldtiana, were known by Indians to produce paralysis. The plant is a shrub indigenous to Texas, Southern California, and Mexico. Dewan et ai.*3 stated that the syndrome known as “limber leg” has been recognized in sheep and goats in areas where this plant grows. It is characterized by progressive leg weakness with associated incoordination and ataxia. The animal finally becomes recumbent and dies. In feeding studies using goats, clinical signs of intoxication may be produced within a few days of the feeding of the berries of this plant. Widespread skeletal and cardiac muscle degeneration were found histologically in all of the animals on the diet. The fruit of the plant is also toxic to man, and several cases of its toxicity have been recorded.

68 FRANK R. BLOOD AND GUILFORD G. RUDOLPH In 1951, Pinder* isolated an alkaloid from yams, Dioscorea hispida, that was toxic to animals. He showed that an a,8- unsaturated lactone was present and the empirical formula was C;3H19Q2N. The structural formula for this alkaloid, dioscorine, has been reported by Pinder.35 76 A similar alkaloid has been isolated from Dioscorea dumetorum, the yam common to Nigeria. It has been shown to be a convulsant, and it may produce death.3” It has the formula C;3;3HyO2N and differs by two hydrogens from the alkaloid isolated from D. hispida. Its ultraviolet and infrared spectra are different than those of dioscorine. The alkaloid isolated from the D. dumetorwn has an LDs0 in mice of 65 mg/kg of body weight. A dose of 20 mg/kg in the cat causes alteration in the responses of blood pressure to acetylcholine and adrenalin. The de- pressor effect of acetylcholine is reduced and the pressor effect of adrenalin is enhanced. In contrast, dioscorine does not potentiate the action of adrenalin on the cat’s blood pressure. Emery described symptoms of stupor, general relaxation, and dila- tion of the pupils when locust bark, Robinia pseudoacacia, was in- gested.38 These symptoms were similar to an overdose of belladonna. Black locust, a small coarse-barked tree, contains a toxic material that produces anorexia, lassitude, weakness, and nausea, with marked dilation of the pupils and, in severe cases, marked dyspnea.39 Several cases of human poisoning are on record, particularly in children who consumed the seeds of this tree. Especially noteworthy is a case of poisoning of 32 boys in a Brooklyn orphan asylum in 1887. For some reason, they ate the inner bark of black locust fence posts which were being stripped in the orphanage yard.38 Much confusion exists in the literature concerning poisoning by ingestion of Atropa belladonna L. Reports of poisoning in the United States and Canada are believed to involve incorrect identification of the plant. The plant has black berries and children may be attracted to them with toxic effects resulting from ingestion. The poisonous prin- ciple is an alkaloid, and a few berries (three for children) contain enough to cause death. Upon ingestion of the berries or alkaloid the symptoms are dryness of the mouth and throat, dilation of the pupils, and tachycardia. Terminal phenomena are depression, exhaustion, and coma.‘ The Death camas. Zigadenus venenosus, is a poisonous plant of the lily family which grows in the Pacific Northwest and British Columbia. It contains dangerous quantities of alkaloids having toxic properties resembling those of beratrin, aconite, and digitalis. It is similar to the edible plant, camas, which was an important food for the Indians and

STIMULANTS AND DEPRESSANTS 69 white settlers. Because of this similarity, the two are easily confused. The alkaloids from the toxic plant act on the cardiovascular system through the vagus with a resulting decrease in blood pressure. The victims be- come drowsy and comatose. The plant, Carolina jessamine, Gelsemium sempervirens, is also known as yellow jessamine and evening trumpetflower. It is found in areas from Virginia to Texas, and the plant contains a number of alkaloids related to strychnine. This plant is generally considered poisonous to all classes of livestock and is ranked as the tenth worst poisonous plant in North Carolina. Children have been poisoned by sucking the nectar from the flowers. Symptoms are depression with respiratory failure and death.42 It has been reported that honey made from the gelsemium nectar has caused death in man. Under range conditions, animals that have eaten the plant are usually found prostrate, and prior to the time they become recumbent, they exhibit muscular weakness, staggering, dilated pupils, and convulsive movements. Death usually occurs within 24 to 48 hours after the animal becomes prostrated.42 In an effort to explain the high incidence of neurological disease on Guam, it has been suggested that the condition that is characterized by lateral sclerosis may be caused by the ingestion of the seeds of the cycad, Cycas circinalis L. These seeds constitute a valuable reserve source of starch for the people of Guam and are used during periods of food scarcity. It has been known for many years that the seeds produce acute toxic effects.44 In animals fed cycads, irreversible and progressive paralysis has resulted, but there has not been any evidence of direct neurological damage. This plant is one hundred times as common on Guam as it 1s in the United States. During the husking of the nuts, a strong acrid odor may actually cause dizziness. The nuts are thought to contain cyanogen or cyanide-releasing compounds. The dried latex of wild lettuce (Latuca virosa) has long been thought to have a sedative action and has been used as a hypnotic. Present in the dried latex is a mixture of alcohols which have been separated and characterized. In addition, two bitter principles, lactucin and lactuco- picrin, the latter present also in chicory and endive, have been isolated and their structures determined.4445 The identity of the sedative com- ponent of the latex has not been definitely established. REFERENCES 1. E. S. Dean, ‘‘Self-induced Stramonium Intoxication,” J. Am. Med. Assoc., 185, 882 (1963).

70 10. 11. 12. 13. 14, 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 26. 27. 28. FRANK R. BLOOD AND GUILFORD G. RUDOLPH H. Jacobziner and H. W. Raybin, “Briefs on Accidental Chemical Poisonings in New York City,” N.Y. State J. Med., 60, 3139 (1960); 6/, 301 (1961). R. E. Jennings, ‘““Stramonium Poisoning; A Review of the Literature and Report of Two Cases,” J. Pediat., 6, 657 (1935). R. K. Gibson, “Jimson Weed Poisoning in Children,” J. Indiana Med. Assoc., 54, 1018 (1961). J. D. Hughes and J. A. Clark Jr., “‘Stramonium Poisoning. A Report of Two Cases,” J. Am. Med. Assoc., 112, 2500 (1939). J. M. Arena, “Atropine Poisoning: A Report of Two Cases from Jimson Weed,” Clin. Pediat., 2, 182 (1963). J. E. Mitchell and F. N. Mitchell, “Jimson Weed (Datura stramonium) Poisoning in Childhood,” J. Pediat., 47, 227 (1955). F. C. Stiles, ““Stramonium Poisoning,” J. Pediat., 39, 354 (1951). W. Mayer-Gross, “‘Experimental Psychoses and Other Mental Abnormalities Produced by Drugs,” Brit. Med. J., il, 317 (1951). R. C. Green Jr., ““Nutmeg Poisoning,” Virginia Med. Monthly, 86, 586 (1959). R. C. Green Jr., ““Nutmeg Poisoning,” J. Am. Med. Assoc., 171, 1342 (1959). G. Weiss, ‘“‘Hallucinogenic and Narcotic-like Effects of Powdered Myristica (Nutmeg),”’ Psychiat. Quart., 34, 346 (1960). E. B. Truitt Jr., E. Callaway, III, M. C. Braude, and J. C. Krantz, Jr., ““The Pharmacology of Myristicin. A Contribution to the Psychopharmacology of Nutmeg,” J. Neuropsychiat., 2,205 (1961). E. B. Truitt Jr., G. Duritz, and E. M. Ebersberger, ‘Evidence of Monoamine Oxidase Inhibition by Myristicin and Nutmeg,”’ Proc. Soc. Exptl. Biol. Med., 112, 647 (1963). H. O. Akesson and J. Walinder, “Nutmeg Intoxication,” Lancet, i, 1271 (1965). F. Kerdel-Vegas, ‘“‘Generalized Hair Loss Due to the Ingestion of ‘Coco de Mono’ (Lecythis ollaria),” J. Invest. Dermatol., 42,91 (1964). D. E. M. Moody and D. P. Moody, “Toxic Products in Groundnuts (Arachis hypogaea),” Nature, 198, 294 (1963). A. F. Hartmann, Sr., A. F. Hartmann, Jr., M. L. Purkerson, and M. E. Wesley, **Tremetol Poisoning—Not Yet Extinct,” J. Am. Med. Assoc., 185, 706 (1963). A. Melville and F. N. Fastiev, “Detection of Certain Honey Poisons,” Proc. Univ. Otago Med. School, 42, 3 (1964); Info. Bull. BIBRA, 3, 585 (1964). E. Cremer and M. Riedmann, “Identifizierung von gaschromatographisch getrennten Aromastoffen in Honigen,” Z. Naturforsch., 19B, 76 (1964); Info. Bull. BIBRA, 3, 176 (1964). D. R. Haggerty and J. A. Conway, “Report of Poisoning by Cicuta maculata (Water Hemlock),” N.Y. State J. Med., 36, 1511 (1936). E. F. L. J. Anet, B. Lythgoe, M. H. Silk, and S. Trippett, ““Oenanthotoxin and Cicutoxin. Isolation and Structure,” J. Chem. Soc., 309 (1953). J. M. Kingsbury, Poisonous Plants of the United States and Canada, Prentice- Hall, Englewood Cliffs, N.J. (1964). lbid., p. 286. . lbid., p. 412. Ibid., p. 325. Ibid., p. 282. Ibid., p. 125.

STIMULANTS AND DEPRESSANTS 71 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. Anon., “Cola Drinks,” J. Am. Med. Assoc., 156, 1376 (1954). L. S. Goodman and A. Gilman, The Pharmacological Basis of Therapeutics, 3rd ed., Macmillan, New York (1965), p. 354. V. A. Drill, ed., Pharmacology in Medicine, 2nd ed., McGraw-Hill, New York (1958), p. 299. A. C. Nolke, “Severe Toxic Effects from Aminophylline and Theophylline Suppositories in Children,” J. Am. Med. Assoc., 161, 693 (1956). M. L. Dewan, J. B. Henson, J. W. Dollahite, and C. H. Bridges, ““Toxic Myode- generation in Goats Produced by Feeding Mature Fruits from the Coyotillo Plant (Karwinskia humboldtiana),” Am. J. Pathol., 46,215 (1965). A. R. Pinder, “An Alkaloid of Dioscorea hispida, Dennstedt,” Nature, 168, 1090 (1951). A. R. Pinder, “An Alkaloid of Dioscorea hispida, Dennstedt, Part I. The Lactone Ring,” J. Chem. Soc., 2236 (1952). A. R. Pinder, “An Alkaloid of Dioscorea hispida, Dennstedt, Part II. Hofmann Degradation,” J. Chem. Soc., 1825 (1953). C. W. L. Bevan, J. L. Broadbent, and J. Hirst, ““A Convulsant Alkaloid of Dioscorea dumetorum,” Nature, 177, 935 (1956). Z. T. Emery, “Poisoning by Locust Bark,” N.Y. State Med. J., 45, 92 (1887). J. M. Kingsbury, Poisonous Plants of the United States and Canada, Prentice- Hall, Englewood Cliffs, N.J. (1964), p. 353. A. A. Forsyth, “British Poisonous Plants,” Ministry of Agr. Fisheries, and Food (London) Bull., 161 (1954) in J. M. Kingsbury, Poisonous Plants of the United States and Canada, Prentice-Hall, Englewood Cliffs, N.J. (1964), p. 275. K. Cameron, “‘Death Camas Poisoning,” Northwest Med., 51, 683 (1952). J. M. Kingsbury, Poisonous Plants of the United States and Canada, Prentice- Hall, Englewood Cliffs, N.J. (1964), p. 260. **Conference on the Cycad,” Public Health Rept. (U.S.), 77, 615 (1962). D. G. Crosby, “‘The Organic Constituents of Food. I. Lettuce,” J. Food Sci., 28, 347 (1963). T. H. Sollmann, A Manual of Pharmacology and Its Application to Therapeutics and Toxicology, 8th ed., W. B. Saunders, Philadelphia (1957), p. 317.

HERBERT C. MANSMANN, JR. Foods as Antigens and Allergens* The capacity of foods to act as antigens and allergens in man and animals is the subject of this chapter. Although those working in this area are aware of the complex nature of the immunological reactions to a food acting as an antigen, the general reader is often confused by a report of an isolated food inducing a specific immune response such as “‘milk precipitins.” The formation of specific immune components after exposure to a food will be discussed, therefore, along with reference to re-exposure reactions as a result of specific sensitization. Such reactions may manifest themselves as a form of food intolerance; thus it becomes necessary to differentiate immunological from nonimmunological intolerance. Recent biochemical and physical-chemical advances have led to the separation of the various immunological components of the immune system, thus adding new procedures for the evaluation of food intolerance. In addition, the same chemical advances have in some instances been applied to the analysis of the constituents of certain foods. Since clinical observations in man have so far failed to keep pace with these recent advances, it is hoped that this review will serve as a stimulus to a more comprehensive and correlative evaluation of immunological food intolerance, as distinct from nonimmunological food intolerance by the study of chemically definable immune and food components. From the reviewed literature, selected references are cited that tend to illustrate the above-stated thesis. The rapid progress in this field is evident by the number of recent articles; however, not all of the foods * The author gratefully acknowledges the technical and editorial assistance of Mrs. Edward Saitz and Mrs. Barbara Magison. 72

ANTIGENS AND ALLERGENS 73 that have been investigated immunologically can be included in this review. Moreover, it is not within the scope of this chapter to discuss the manifestations of immunological reactions, for this literature is readily available.!12 Whether a food is acting as an antigen or as an allergen depends upon the identification of the immunological system responding. A distinction, therefore, will be made when a specific food component is functioning as an antigen or as an allergen. TERMINOLOGY It is the author’s desire to eradicate the existing confusions that occur in regard to the mystic connotations of the loosely used clinical diag- nostic words “food allergy.” Therefore, the more significant termi- nology of immunological and nonimmunological food intolerances will be used. In many instances confusion arises because of species variations and because of the lag between scientific and semantic development. Food For this discussion, a food is any substance that is ordinarily consumed by humans. Each food is a mixture of many chemical compounds. This number is increased by digestive processes that alter their chemical configurations. Finally, the matter is complicated further because molecules contain several antigenic sites, each of which can induce a specific immunological component. Antigen An antigen is a chemically definable substance that, because it is foreign to the animal, induces one or more specific immune components. Also, an antigen has the capacity to react specifically, in vivo or in vitro, with its induced homologous immune component. Antigenicity Antigenicity is the capacity of an antigen to stimulate in an animal the production of a specific component of one or more of the immune mechanisms.

714 HERBERT C. MANSMANN, JR. Allergen An allergen is an antigen that induces in certain individuals a specific antibody called ‘“‘reagin” and it has the capacity to participate in an allergic reaction upon subsequent re-exposure. Allergenicity Allergenicity is the capacity of an allergen to induce the production of reagin in susceptible animals or human subjects. Classical Antibodies Classical antibodies are currently referred to as immunoglobulin G (IgG) on the basis of characterization by ultracentrifugation, electro- phoresis, and column chromatography. The heterogeneity of the y-globulins has been the subject of a recent review.!° The specificity of these antibodies can be demonstrated by antigen-antibody precipitating systems. These antibodies are stable on exposure to 56°C for 4 hours and are unable to sensitize human skin, hence, they are clearly separate biologically from reagin. Reaginic Antibodies Reagins*6 are found in the immunoglobulin A fraction (IgA) of atopic individuals and are essential to the immediate wheal and flare skin reactions. They are frequently referred to as atopic and skin-sensitizing antibodies. Twenty to 40 percent of the human population produces reagins spontaneously as a result of natural exposure to certain aller- gens, and some of these persons are clinically allergic. Reaginic anti- bodies are destroyed by heating at 56°C for 0.5 to 4 hours. Delayed Hypersensitivity Component Another result of antigenic stimulation is the induction of the state of delayed hypersensitivity, frequently referred to as “‘tuberculin-type” hypersensitivity, which is basically a specific cellular reactivity to an antigen.3 Although frequently referred to as a cellular antibody, this is not a y-globulin and has in common with an antibody only its antigen specificity.