Toxicants Occurring Naturally in Foods. (1966)

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SEAFOOD TOXINS 159 and when poisoning becomes apparent within a few hours after inges- tion of food. Thereafter, supportive treatment, including artificial ventilation when necessary, is about all that is available. In paralytic shellfish poisoning of laboratory animals, d/-amphetamine was found to be a valuable adjunct to artificial ventilation. In puffer fish poisoning of laboratory animals, there is some suggestion that pentylenetetrazol is a useful adjunct to artificial ventilation. Once the chemical natures and modes of action of the toxic principles are known, it should be possible to devise a rational therapy for each of these intoxications. Some general rules that appear to be useful for avoiding intoxication are not to eat gonads or skin, to soak the flesh of suspected toxic fish in several changes of clean salted water before cooking, and not to depend on cooking to destroy toxic substances. For example, the poison of paralytic shellfish poisoning is known to withstand boiling, except in a definitely alkaline solution, for a considerable time. REFERENCES 1. P. Martyr, De Orbe Novo, “The Eight Decades of Peter Martyr d’Anghera” (1555). Quoted in E. W. Gudger, “‘Poisonous Fishes and Fish Poisonings, with Special Reference to Ciguatera in the West Indies,” Am. J. Trop. Med., 10, 45 (1930). 2. B. W. Halstead and W. M. Lively, Jr., “Poisonous Fishes and Ichthyosarco- toxism,”” U.S. Armed Forces Med. J., 5, 157 (1954). 3. B. W. Halstead, ‘Poisonous Fishes,” Public Health Repts. (U.S.), 73, 302 (1958). 4. S. C. Cohen, J. T. Emert, and C. C. Goss, “Poisoning by Barracudalike Fish in the Marianas,” U.S. Med. Bull., 46, 311 (1946). 5. R. J. Ralls and B. W. Halstead, “‘Moray Eel Poisoning and a Preliminary Report on the Action of the Toxin,” Am. J. Trop. Med., 4, 136 (1955). 6. W. Markov, “‘Seefischvergiftung,” Wien. Med. Wochschr., 93, 388 (1943). 7. E. Geiger, G. Courtney, and G. Schnakenberg, “The Content and Formation of Histamine in Fish Muscle,” Arch. Biochem., 3, 311 (1944). 8. T. Kawabata, K. Ishizaka, and T.' Miura, “Studies on the Allergy-like Food Poisoning Associated with Putrefaction of Marine Products. II. Separation of Causative Substance and Some of Its Chemical Characteristics,” Japan. J. Med. Sci. Biol., 8, 503 (1955). 9. T. Kawabata, K. Ishizaka, and T. Miura, “‘Studies on the Allergy-like Food Poisoning Associated with Putrefaction of Marine Products. III. Physiological and Pharmacological Action of ‘Saurine’, a Vagus Stimulant of Unknown Structure Recently Isolated by the Authors, and Its Characteristics in Develop- ing Allergy-like Symptoms,” Japan. J. Med. Sci. Biol., 8, 521 (1955). 10. T. Kawabata, B. W. Halstead, and T. F. Judefind, ““A Report of a Series of Recent Outbreaks of Unusual Cephalopod and Fish Intoxications in Japan,” Am. J. Trop. Med. Hyg., 6, 935 (1957).

23. 24. 25. 26. 27. 28. 30. 31. 32. 33. 34, J. H. WILLS, JR. . E.K. Suvorov, Osnovy Ikhtiologii, Sovetskaya Nauka, Moskva (1948). T. Kawabata, “Fish-borne Food Poisoning in Japan,” in Fish as Food, Vol. 2, G. Borgstrom, ed., Academic Press, New York (1962), pp. 467-479. . J. Pellegrin, Les poissons veneneux, Ollier-Henry, Paris (1899). M. Phisalix-Picot, Animaux venimeux et venins, Masson et Cie, Paris (1922). B. W. Halstead and N. C. Bunker, “A Survey of the Poisonous Fishes of the Phoenix Islands,” Copeia, No. I, 1 (1954). . A. Chevallier and E. A. Duchesne, “‘Memoire sur les empoisonnements par les huitres, les moules, les crabes, et par certains poissons de mer et de riviere,”’ Ann. Hyg. Publ., 45, 387 (1851). R. Kobert, “‘Uber Giftfische und Fischgifte,” Med. Wochschr., 20, 209 (1902). . H. Engelsen, “Om giftfisk og giftige fisk,”” Nord. Hyg. Tidskr., 3, 316 (1922). . H. Coutand, “Observations sur sept cas d’empoisonnement par le foi de requin a |’Ile des Pins (Nouvelle Caledonie) en 1873,” These, Montpellier (1879). A. S. Jensen, “The Selachians of Greenland,” Mindeskr. Steenstrup, 30, 12 (1914). . M. Mizuta and M. Mizobe, “*Food Poisoning from Eating Livers of ‘Sawara’ and ‘Iwashi-Kujira’,”” Nippon Iji-Shinpo, 1710, 27 (1957). P. Helfrich, Fish Poisoning in the Tropical Pacific, University of Hawaii Marine Laboratory, Honolulu (1961). E. W. Gudger, “‘A New Purgative, the Oil of the ‘castor oil fish,’ ruvettus,” Boston Med. Surg. J., 192, 107 (1925). D. J. Macgowan, Report on the Health of Wenchow for the Half-Year Ended 30th September 1883, Chin. Imp. Maritime Customs, Med. Rept., 26th Issue, Statistical Dept. Inspectorate Gen. Customs, Shanghei (1884), pp. 64-72. D. J. Macgowan, Report on the Health of Wenchow for the Half-Year Ended 3Ilst March 1884, Chin. Imp. Maritime Customs, Med. Rept., 27th Issue, Statistical Dept. Inspectorate Gen. Customs, Shanghai (1884), pp. 9-18. K. F. Meyer, H. Sommer, and P. Schoenholz, ‘‘Mussel Poisoning,” J. Prev. Med., 2, 365 (1928). E. F. McFarren, M. L. Schafer, J. E. Campbell, K. H. Lewis, E. T. Jensen, and E. J. Schantz, “Public Health Significance of Paralytic Shellfish Poison,” Advan. Food Res., 10, 135 (1960). T. Akiba, “Study of Poisoning by Venerupis semidecussata and Ostrea gigas and Their Poisonous Substances,” Nisshin Igaku, 36, 231 (1949). T. Itai and S. Kamiya, “‘Studies on Lake Hamana Oyster and Other Shellfiish for Poisonous Substances II,” Eisei Shikensho Hokoku, 74, 283 (1956). S. Takenaka, G. Sawada, and M. Yoshioka, “On the Poisonous Sea-ear, or Haliotis tuberculata,” Tokyo Iji Shinshi No. 1114, 1359 (1899). B. W. Halstead and D. W. Schall, “‘A Report on the Poisonous Fishes of the Line Islands,” Acta Trop., 15, 193 (1958). C. J. Fish and M. C. Cobb, Noxious Marine Animals of the Central and Western North Pacific, U.S. Fish and Wildlife Service Res. Rept., 36, iii, U.S. Govt. Printing Office, Washington, D.C. (1954). B. W. Halstead, “Poisonous Fishes and Their Relationship to Marine Food Resources in the Pacific Area,” in Proc. 8th Pacific Sci. Congr. Pacific Sci. Assoc., Quezon City, 1953, Natl. Res. Council of the Philippines, Quezon City (1958), Vol. 3, p. 321. Y. E. Dawson, “Changes in Palmyra Atoll and Its Vegetation Through the Activities of Man, 1913-1958,” Pacific Natural., 1, 1(1959).

SBAFOOD TOXINS 161 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 51. 52. 53. 55. J. E. Randall, “‘A Review of Ciguatera, Tropical Fish Pcisoning, with a Tenta- tive Explanation of Its Cause,” Bull. Marine Sci. Gulf Carib., 8, 236 (1958). A. H. Banner, P. J. Scheuer, S. Sasaki, P. Helfrich, and C. B. Alender, ““Observa- tions on Ciguatera-type Toxin in Fish,” Ann. N.Y. Acad. Sci., 90, 770 (1960). D. W. Hessel, “Marine Biotoxins. II. The Extraction and Partial Purification of Ciguatera Toxin from Lutjanus bohar (Forskal),” Toxicol. Appl. Pharmacol., 3, 574 (1961). P. Helfrich and T. Yoshida, quoted (p. 620) by B. W. Halstead, in “Fish Poisonings—Their Diagnosis, Pharmacology and Treatment,” Clin. Pharmacol. Therap., 5, 615 (1964). B. W. Halstead and D. W. Hessel, private communication (June 1961). P. Helfrich and A. H. Banner, ‘‘Experimental Induction of Ciguatera Toxicity in Fish Through Diet,” Nature, 197, 1025 (1963). K.-M. Li, “Ciguatera Fish Poison: A Cholinesterase Inhibitor,’ Science, 147, 1580 (1965). F. Ghiretti and E. Rocca, ‘“‘Some Experiments on Ichthyotoxin,” in Venemnous and Poisonous Animals and Noxious Plants of the Pacific Region, H. L. Keegan, ed., Macmillan, New York (1963). R. Jaques, “‘A Substance from Eel Serum Producing Slow Contractions,” Nature, 175, 212 (1955). G. Buglia, “‘Ricerche suJla natura de veleno dell’anguilla. VII. Della sostanza che emolizza il sangue,”’ Atti Soc. Toscana Sci. Nat. Pisa Proc. Verbali Mem., 34, 87 (1922); see also Arch. Ital. Biol., 72, 81 (1923). B. W. Halstead, ‘“‘Biotoxications, Allergies, and Other Disorders,” in Fish as Food, Vol. 2,G. Borgstrom, ed., Academic Press, New York (1962), pp. 521-540. E. Geiger, *“‘Histamine Content of Unprocessed and Canned Fish. A Tentative Method for Quantitative Determination of Spoilage,” Food Res., 9, 293 (1944). R. Legroux, J. C. Levaditi, G. Boudin, and D. Bovet, “Intoxications hista- miniques collectives consecutives a l’ingestion de thon frais,” Presse Med., 29, 545 (1946). . W.H. Yudkin, “Tetrodon poisoning,” Bull. Bingham Ocean. Coll., 9, 1 (1944). . J.T. Nichols and P. Bartsch, Fishes and Shells of the Pacific World, Macmillan, New York (1945). . K. Tsuda and M. Kawamura, “Constituents of the Ovaries of Globefish VII. Purification of Tetrodotoxin by Chromatography,” J. Pharm. Soc. Japan, 72, 771 (1952). H. S. Mosher, F. A. Fuhrman, H. D. Buchwald, and H. G. Fischer, ““Taricha- toxin—Tetrodotoxin: A Potent Neurotoxin,” Science, 144, 1100 (1964). F. Ishihara, ““Tetrodon Poison and Some of Its Chemical Characteristics,” Tokyo Igakukai Zasshi, 31, 1 (1917). K. Iwakawa and S. Kimura, “‘Experimentelle Untersuchungen iiber die Wirkung des Tetrodontoxins (‘Fugugift’),”, Arch Exptl. Pathol. Pharmakol., 93, 305 (1922). . I. Yano, “An Experimental Study on the Globe-fish (Fugu) Intoxication,” Japan. J. Med. Sci. VIIT. Intern. Med., Pediatry, Psychiatry, 5,99 (1938). D. B. Horsburgh, E. L. Tatum, and V. E. Hall, ““Chemical Properties and Physiological Actions of Triturus Embryonic Toxic,” J. Pharmacol. Expil. Therap., 68, 284 (1940).

162 J. H. WILLS, JR. 56. S. Nagayosi, “On Intraocular Tension, Particularly on the Relation between Eye, Blood and Spinal Fluid Pressures,” Hukuoka Acta Med., 34, 312 (Abst. Sect. 39), (1941). 57. R. S. Turner and F. A. Fuhrman, “Modification of the Action Potential of Amphibian Nerves by Jriturus Embryonic Toxin,” Am. J. Physiol., 150, 325 (1947). 58. M. Matsumura and S. Yamamoto, “‘The Effect of Tetrodotoxin on the Neuro- muscular Junction and Periphere! Nerve of the Toad,” Japan. J. Pharmacol., 4, 62 (1954). 59. E. F. Murtha, D. E. Stabile, and J. H. Wills, “Some Pharmacological Effects of Puffer Poison,” J. Pharmacol. Exptl. Therap., 122, 247 (1958). 60. T. Furukawa, T. Sasaoka, and Y. Hosoya, “Effects of Tetrodotoxin on the Neuromuscular Junction,” Japan. J. Physiol., 9, 143 (1959). 61. W. D. Dettbarn, H. Higman, P. Rosenberg, and D. Nachmansohn, “Rapid and Reversible Block of Electrical Activity by Powerful Marine Biotoxins,” Science, 132, 300 (1960). 62. E. F. Murtha, “Pharmacological Study of Poisons from Shellfish and Puffer Fish,” Ann. N.Y. Acad. Sci., 90, 820 (1960). 63. J. H. Fleisher, P. J. Killos, and C. S. Harrison, “Effects of Puffer Poison on Neuromuscular Transmission,” J. Pharmacol. Exptl. Therap., 133, 98 (1961). 64. J. Cheymol, P. Foulhoux, F. Bourillet, and P. Simon,“ Action de Ja tetrodotoxine sur les phenomenes electriques de la transmission neuromusculaire,” Cornpt. Rend. Soc. Biol., 156, 602 (1962). 65. T. Hayama and Y. Ogura, “Site of Emetic Action of Tetrodotoxin in Dog,” J. Pharmacol. Exptl. Therap., 139, 94 (1963). 66. C. Y. Kao and F, A. Fuhrman, “Pharmacological Studies on Tarichatoxin, A Potent Neurotoxin,” J. Pharmacol. Exptl. Therap., 140, 31 (1963). 67. W.R. Loewenstein, C. A. Terzuolo, and Y. Washizu, “Separation of Transducer and Impulse-Generating Processes in Sensory Receptors,”’ Science, 142, 1180 (1963). 68. H.L. Borison, L. E. McCarthy, W. G. Clark, and N. Radhakrishnan,“Vomiting, Hypothermia and Respiratory Paralysis Due to Tetrodotoxin (Puffer Fish Poison) in the Cat,” Toxicol. Appl. Pharmacol., 5, 350 (1963). 69. N. Ogasawara, K. Tamari, J. Kaji, J. Nakajima, and T. Kojima, “The Toxic Substances Isolated from Poisonous Cuttle-fishes in Niigata Prefecture I. Isolation of a New Toxic Amine,” Niigata Daigaku Nogakubu Gakujutsu Hokoku, No. 9, 79 (1959). 70. D.J. Macht and J. Barba-Gose, “Pharmacology of Ruvettus retiosus or ‘Castor Oil Fish’,” Proc. Soc. Exptl. Biol. Med., 28,772 (1931). 71. J. L. Wilson and D. G. Dickinson, ‘‘Use of Dioctyl Sodium Sulfosuccinate (Aerosol O. T.) for Severe Constipation,” J. Am. Med. Assoc., 158, 261 (1955). 72. E. J. Schantz, J. D. Mold, D. W. Stanger, J. Shavel, F. Riel, J. P. Bowden, J. M. Lynch, R. W. Wyler, B. Riegel, and H. Sommer, “‘Paralytic Shellfish Poison VI. A Procedure for the Isolation and Purification of the Poison from Toxic Clams and Mussel Tissue,” J. Am. Chem. Soc., 79, 5230 (1957). 73. H. Sommer, W. F. Whedon, C. A. Kofoid, and R. Stohler, “Relation of Paralytic Shell-fish Poison to Certain Plankton Organisms of the Genus Gonyaulax,” Arch. Pathol., 24, 537 (1937).

SEAFOOD TOXINS 163 74. 75. 76. 77. 78. 79. 80. 81. 82. Y. Hashimoto and M. Migita, “On the Shellfish Poisons. I. Inadequacy of Acidulated Alcohols with Hydrochloric Acid as Solvent,” Bull. Japan. Soc. Sci. Fish., 16, 77 (1950). J. Hornell, ““A New Protozoan Cause of Widespread Mortality Among Marine Fishes,’’ Madras Fisheries Bull., 11,53 (1917). S. Matoda, Sea and Plankton, Kawade Shobo Publ., Tokyo (1944). J. M. Burke, J. Marchisotto, J. J. A. McLaughlin, and L. Provasoli, ‘Analysis of the Toxin Produced by Gonyaulax catenella in Axenic Culture,” Ann. N.Y. Acad. Sci., 90, 837 (1960). M. Fingerman, R. H. Forester, and J. H. Stover, Jr.,**Action of Shellfish Poison on Peripheral Nerve and Skeletal Muscle,” Proc. Soc. Exptl. Biol. Med., 84, 643 (1953). Y. Hashimoto, K. Naito, and J. Tsutsumi, ‘““Photosensitization of Animals by the Viscera of Abalones, Haliotis spp.,” Japan. Soc. Sci. Fish., 26, 1216 (1960). Y. Hashimoto and J. Tsutsumi, “Isolation of a Photodynamic Agent from the Liver of Abalone, Haliotis discus hannai,”’ Japan. Soc. Sci. Fish., 27, 859 (1961). H. Fischer, O. Moldenhauer, and O. Siis,“*Zur Konstitution des Chlorophyll a. Uber Phaophorbid, Methylphaophorbid und Chlorine,” Ann. Chem., 486, 107 (1931). G. Y. Kennedy and H. G. Vevers, “Porphyrin Pigments in the Tectibranch Mollusc, Akera bullata O. F. Miiller, J. Marine Biol. Assoc. U.K., 35, 35 (1956).

RICHARD L. HALL Toxicants Occurring Naturally in Spices and Flavors Although historical records are lacking, spices are certainly among the first substances, after salt, that man added to his food. These natural aromatics were seldom valued solely for their flavor, for nearly all enjoyed status as drugs, stimulants, aphrodisiacs, or food preservatives. Without much doubt, in most instances their merit lay chiefly in the mind of the user. As effective pharmacological agents became available, and our ability to assess their merits developed, the use of naturally occurring drugs, including the spices, declined. The formularies, pharmacopoeias, and dispensatories of today carry only the surviving remnants of a much larger number, and these primarily because of their use as flavors in pharmaceutical preparations. It is not surprising that almost all our present spices are devoid of physiological effect even in amounts much greater than are normally used in food. This is partly because those few that might present some hazard have been recognized and dropped from use. Beyond this, how- ever, is the fact that in the majority of instances, a naturally occurring toxicant in food is not only detected by taste, odor, or the common chemical sense, but it becomes distinctly unpalatable at a level several orders of magnitude below that at which toxic effects can be observed. The exceptions to this generalization form one of the reasons for this paper, and flavors contain a few of these exceptions. Even these excep- tions, however, can accurately be described as self-limiting. For the purposes of this review, the substances that will be regarded as toxicants naturally occurring in flavors are those in which the customary gap, or safety factor, between levels that are organoleptically acceptable and those that are harmful is markedly narrower than usual, or the con- 164

SPICES AND FLAVORS 165 stituent in question exhibits unusual features of toxicity, such as vesicant or narcotic action, carcinogenesis, or toxicity at extraordinarily low levels. Since toxicity, the capacity of a substance to cause harm, is an absolute property, there is a hazard only if the state of the organism and the conditions and levels of use permit this capacity to be realized. So far as spices and flavors are concerned, the examples of actual harm resulting from their ingestion are so rare as to be medical curiosities. Using these general criteria, there are eight substances that occur naturally in flavoring materials in current or recent use that would probably be included in any list of substances generally regarded as toxic. These are: hydrogen cyanide, found in a number of glycosides; myristicin, in mace, nutmeg, and dill; allyl isothiocyanate, in brown mustard; umbellulone, in California bay laurel; capsaicin, in red pepper; and coumarin, safrol, and thujone, each of which occurs in a number of different species. Hydrogen Cyanide Hydrogen cyanide (HCN) occurs bound chemically in a number of glycosides found in food. Oil of bitter almonds, a generic name for the oils of bitter almonds, apricot kernels, or peach kernels, contains the glycoside amygdalin. The enzyme emulsin is also present, and when the pits are crushed and moistened, the glycoside is cleaved with the libera- tion of hydrogen cyanide (Reaction 1). The leaves of the cherry laurel, € \-crotre + 2H,0 Sinwisin, N Amygdalin ¢ \-c10 +HCN + 20H, Benzalkdehyde Hydrogen Glucose Cyanide (Reaction 1) Prunus laurocerasus L., contain a similar glycoside, prulaurasin, which is also split by emulsin to release benzaldehyde and hydrogen cyanide. While such oils may originally contain up to 11 percent of HCN, the usual level is 2—4 percent.! All oils produced commercially for food use are treated chemically to remove the HCN and are designated FFPA (free from prussic acid). Homemade foods containing these materials, and other natural sources of hydrogen cyanide such as cashew nuts and some brandies, result in the continued consumption of insignificant quantities of the toxicant. Considerable evidence shows that the body

166 RICHARD L. HALL can eliminate small quantities of cyanide, both by conversion to the much less toxic thiocyanate and by combination with cystine. These metabolic routes appear to be capable of handling any quantities in- gested from natural dietary sources, but not the abnormal amounts from environmental or nonfood hazards.2 Allyl Isothiocyanate Brown mustard, Brassica juncea (L.) Coss., contains the glycoside sinigrin and the enzyme myosin. When the seeds are moistened and crushed, glucose, potassium bisulfate, and allyl isothiocyanate result (Reaction 2). Allyl isothiocyanate is a potent irritant; its usefulness as a 0S0,« GgH),Qs-SC=NCH,CH= H, + HzO Osi Sinigrin CeH,Og + KHSO, + CH,= CHCH,NCS p-Glucose Allyl isothiocyanate (Reaction 2) local counterirritant accounts for the listing of mustard in the U.S. Dispensatory. Allyl isothiocyanate has been isolated from horse- radish,3-4 several other members of the genus Brassica, a large group that includes mustard, broccoli, and cabbage, and also from rocket salad, Eruca sativa.’ Although experience in human use is extensive, the literature reports of toxicological data are relatively meager, and simply confirm that in high concentration allyl isothiocyanate is a strong irritant. Rusch et al. report an increase in mitotic activity after a single application to mouse ears.6 Not surprisingly, Cordier and Cordier found it toxic on intravenous injection.’ Umbellulone The leaves of the California bay laurel tree (Umbellularia californica Nutt.) have had considerable past food use, especially for seasoning game. They contain from 0.5 to 4 percent of an irritating oil, of which the major constituent, accounting for from 40 to 60 percent, is umbel- lulone (I). According to Guenther,’ care is advisable to avoid injury while collecting the branches. Drake and Stuhr? mention that proximity to the oil or its vapors has resulted in severe headache, skin irritation, and in some cases unconsciousness. They found umbellulone to produce a decided hemolysis in vivo and compared its effects on the nerves and

SPICES AND FLAVORS 167 CH3 HC CH, I fibers of frog heart with those of atropine. They concluded that it was a depressant, acting in part by blocking of pulmonary circulation. Because other spices, including the traditional bay or laurel (Laurus nobilis L.), are available without this hazard, the California bay laurel has no currently recognized status as an appropriate food ingredient. Capsaicin The substance responsible for the heat, or pungency, of all members of the genus Capsicum, the red peppers, is the amide capsaicin (II).!9-1! It is a highly irritating substance, detectable in water at dilutions of over 1: 1,000,000. Applied in concentrated form to the skin, it is a vesicant. Anyone who has had occasion to consume foods high in capsaicin is familiar with its ability to induce sweating and salivation. These reac- tions and increased gastric flow are apparently reflex actions resulting from the direct effect of capsaicin on the pain fibers in the mucous membranes of the mouth.!2.13 € Nc He (CH) 4 CHaCHCH(CHs), 0 zr Myristicin Nutmeg and mace (both from Myristica fragrans Houtt.) contain from 8 to 15 percent of a volatile oil, which was still listed in U.S.P. XVI as Myristica Oil. About 4 percent of the oil is myristicin (III), its only physiologically active ingredient. Myristicin is also found in a number of members of the carrot family (Umbelliferae), including parsley,'* celery,!5 and dill.!6 The medicinal use of nutmeg and mace goes back at least to the early Middle Ages in the Arab world, and probably earlier in India. Then, these spices enjoyed high esteem as a

168 RICHARD L. HALL CH30 I treatment for a wide variety of conditions including toothache, dysen- tery, cholera, rheumatism, halitosis, and skin diseases. Western medi- cine followed this lead, and improved upon it, until nutmeg came to be thought of as almost a panacea. Disenchantment did not set in until the nineteenth century, during which their scope of application was nar- rowed sharply. At about this time, however, nutmeg acquired in some unknown way the reputation of being an emmenagogue and aborti- facient. This wholly unjustified reputation persists even today and is responsible for a number of cases of nutmeg poisoning.!7 Taken in large quantity, nutmeg and mace exhibit pronounced narcotic and psychomimetic properties, somewhat comparable to alcoholic intoxi- cation.'8 A puzzling aspect of their action is that the effects of the spice are greater than those of an equivalent amount of myristicin, even though the myristicin is the only constituent that separately causes significant physiological response. Very high doses may result in liver damage or death. During the last century, awareness of the narcotic properties of nutmeg led to occasional instances of use for this purpose. Nutmeg is the spice usually chosen for the practical reason that it is cheaper and more readily available. The dosage ordinarily involved in attempts at narcotic or abortifacient use are of the order of two whole nutmegs, or an ounce of the grated product—a quantity far in excess of any conceivable flavor use. There is little evidence that those who try the use of nutmeg as a narcotic indulge in much repetition; the side effects and aftereffects, including headache, cramps, and nausea, are reported to be common, severe, and extremely unpleasant. Truitt et al.!8 advance the supposition that myristicin acts as a weak monoamine oxidase inhibitor. If it follows a metabolic pathway similar to that of safrol (q.v.), it might well be converted in vivo into substances similar to or identical with known psychomimetic agents such as 3-methoxy-4, 5-methylenedioxyamphetamine."” Coumarin Coumarin (IV) is found widely distributed in a number of substances that are natural sources of flavors. While neither it nor its principal natural source, tonka beans [Dipteryx odorata (Aubl.) Willd.] are now

SPICES AND FLAVORS 169 eh. w uesd in food, it is an important flavoring constituent of cassie, Acacia farnesiana (L.) Willd.;!9 lavender, Lavandula officinalis Chaix;20.2! lovage, Levisticum officinale Koch;22 yellow sweet clover, Melilotus officinalis ;> Copaifera lansdorfii;24 deer tongue, Trilisa odoratissima (Walt.) Cass. ;2 and woodruff, Asperula odorata L.*6 Cassie, lavender, and lovage are used rather widely in candy and liqueur flavors, and woodruff is the principal flavor of May wine. Coumarin, used as such, disappeared from flavor use in 1954 follow- ing reports, initially by Hazleton et al.27 and later by Sporn,” of extensive liver damage to rats resulting from the feeding of relatively high levels. Prior to that time, it was widely used as an ingredient of imitation vanilla flavors. Coumarin is metabolized largely by hydroxylation at the 3 and 7 positions, followed by conjugation with glucuronic acid or sulfuric acid, and elimination of the conjugate.29 Safrol One of the most widespread of the essential oil constituents that are now regarded as toxic is safrol (V). It is the major constituent (85 per- cent) of the oil of sassafras, the oil of the root bark of Sassafras albidum ‘ CHCH=CH, HC ZX (Nutt.) Nees.3° It forms 95 percent of micranthum oil, from Cinna- momum micranthum Hayata, and occurs in several related species and varieties.3! 32 It is also found in mace and nutmeg,33 Japanese wild ginger,*4 California bay laurel,35 and a number of other species. In toxicological studies carried out by the United States Food and Drug Administration, Lehman reported that the continuous admin- istration of safrol at high levels in the total diet of rats caused liver tumors, and that lower levels produced lesser noncancerous damage.

170 RICHARD L. HALL Although the evidence suggested that a low safe level of use could be established, safrol and those oils of which it is the major constituent have been dropped from use because of the provision of the Food Additives Amendment of 1958 excluding from use in food, substances which, in the diet of man or experimental animals, are found to cause cancer. Little metabolic work has been done, but piperonylic acid has been found to be a metabolite of safrol and isosafrol after administration to dogs.3? Thujone The flavor constituent that first gained toxicological notoriety is thujone (VI). It is a major component of oil of wormwood, Artemisia absinthium L., the principal flavoring ingredient of the liqueur H3 0 ww absinthe.38 Serious physiological consequences resulting from the excessive use of this beverage, particularly in France, led to a cam- paign that resulted in its abolition there in 1915. Wormwood continues to be used in trace quantities in flavored wines such as vermouth. Toxicity studies have shown that, in sufficient quantity, thujone pro- duces convulsions associated with lesions of the cerebral cortex.39—4! Thujone occurs in two stereoisomeric forms one of which is called a,l, or (—) thujone, and the other 8,d, or (+) isothujone. Both thujones occur in several species of the genus Artemisia42-4 Both forms are present in oil of wormwood and in oak moss, Evernia prunastri (L.) Ach, and E. furfuracea (L.) Mann.“6 The a form is the major con- stituent of cedar leaf oil (oil of thuja), from Thuja occidentalis L.,4748 and is an important component of sage, Salvia officinalis L.495° Tansy, Tanacetum vulgare L., contains the 6 form,5!52 as does yarrow, Achillea millefolium L.°3 Little is known of the metabolism of thujone. In the rabbit, at least a portion may be converted by hydroxylative cleavage of the bridge link to the tertiary alcohol and excreted as the glucuronide.

SPICES AND FLAVORS 171 One cannot avoid noting the close relationship in chemical structure between myristicin and safrol and between thujone and umbellulone. At this stage of our knowledge, it would be risky to draw conclusions from these relationships, since other substances equally closely related lack the physiological effects of those discussed here. It is now evident that while some substances are limited in known occurrence to a single species, others, such as coumarin, safrol, and thujone, are found, at least in traces, in species not merely of several different genera, but of quite unrelated families. Unpublished data indicate, in several cases, far broader distribution than that sum- marized here. As more sensitive methods of separating and identifying the components of essential oils are developed and applied, one may expect to find that at least some of these relatively toxic materials are nearly ubiquitous, and that we must continue to rely upon the re- markable capacity of the human body to deal promptly and effectively with small quantities of toxic materials. REFERENCES 1. E. Guenther, The Essential Oils, Van Nostrand, New York (1952), Vol. 5, p. 52. 2. R. T. Williams, Detoxication Mechanisms, 2nd ed., Wiley, New York (1959), p. 390. 3. A. Guillaume, “Horse-radish and Its Applications,” Prod. Pharm., 6, 383 (1951). 4. G. Janiéek and A. Capek, “Volatile Phytoncide of Horse-radish,” Prumysi Potravin, 5, 204 (1954). 5. A. Mohammad and S. Ahmad, “‘A Note on Essential Oi! of Mustard in Brassica Species and Eruca sativa,” Indian J. Agr. Sci., 15, 181 (1945). 6. H. P. Rusch, D. Bosch, and R. K. Boutwell, “The Influence of Irritants on Mitotic Activity and Tumor Formation in Mouse Epidermis,” Acta Unio Intern. Contra Cancrum, 11, 699 (1955). 7. D. Cordier and G. Cordier, “Mode of Action of bis(2-Chloroethyl) Sulfide on the Cardiovascular System; Effects of Chemically Similar Compounds,” Compt. Rend. Soc. Biol., 145, 1310 (1951). 8. E. Guenther, The Essential Oils, Van Nostrand, New York (1950), Vol. 4, p. 207. 9. M. E. Drake and E. T. Stuhr, ““Some Pharmacological and Bactericidal Proper- ties of Umbellulone,” J. Am. Pharm. Assoc. Sci. Ed., 24, 196 (1935). 10. H. Pella de la Flor, “Chemical Study of Capsicum frutescens. Capsaicine Con- tent,” Anales Fac. Farm. Bio-Quim., Univ., Nacl. Mayor San Marcos (Lima), 5, 206 (1954). 11. M. Nujfiez-Samper, ‘Capsaicin, Its Content and Colorimetric Determination in Capsicum,” Anales Bromatol. (Madrid), 3, 323 (1951). 12. C. C. Toh, T. S. Lee, and A. K. Kiang, ‘““The Pharmacological Actions of Capsaicin and Analogs,” Brit. J. Pharmacol., 10, 175 (1955).

172 RICHARD L. HALL 13. J. Pérszdsz, L. Gyorgy, and K. Gibiszer-P6érsz4sz, “Cardiovascular and Respira- tory Effects of Capsaicin,” Acta Physiol. Acad. Sct. Hung., 8, 60 (1955). 14. J. Small, “Parsley Seed,” Food, 18, 268 (1949). 15. M. Karmazin, “Critical Examination of Celery Fruit and Root on the Basis of a Colorimetric Determination of Apiol and Myristicin,” Pharmazie, 10, 57 (1955). 16. Ann. Rept., Schimmel & Co. (1927), pp. 36-37. 17. A. T. Weil, “Nutmeg as a Narcotic,” Econ. Botany, 19, 194 (1965). 18. E.B. Truitt, Jr., E. Callaway III, M. C. Braude, and J. C. Krantz, Jr., “*Pharma- cology of Myristicin, A Contribution to the Psychopharmacology of Nutmeg,” J. Neuropsychiat., 2, 205 (1961). 19. D. La Face, “The Concrete Essence of Acacia farnesiana,” Helv. Chim. Acta, 33, 249 (1950). 20. C. Kleber, “‘Acetates in Oil of Lavender,” Am. Perfumer, 21, 680 (1927), and a letter of comment by A. St. Pfau, Am. Perfumer Essent. Oil Rev., 22, 275 (1927). 21. C. F. Seidel, H. Schinz, and P. H. Miller, “Lavender Oil. III. Monoterpene Alcohols and Acids Occurring as Esters in French Lavender Oil,”? Helv. Chim. Acta, 27, 663 (1944). 22. Y. R. Naves, “Volatile Plant Materials. XXIV. Composition of the Essential Oil and Resinoid of Lovage Root,” Helv. Chim. Acta, 26, 1281 (1943). 23. J. M. Slatensek, ““Some Causes for Variation of Coumarin Content in Sweet Clover,” J. Am. Soc. Agron., 39, 596 (1947). 24. W. B. Mors and H. J. Monteiro, ““Two Coumarins in the Seed of Copaifera langsdorflii,”” Anais Assoc. Brasil. Quim., 18, 181 (1959). 25. A. Osol and G. E. Farrar, Jr., eds., The Dispensatory of the United States oj America, 25th ed., Lippincott, Philadelphia, Pa. (1955), p. 398. 26. The Merck Index, 7th ed. Merck & Co., Rahway, N.J. (1960), p. 1105. 27. L. W. Hazleton, T. W. Tusing, B. R. Zeitlin, R. Thiessen, Jr., and H. K. Murer, ““Toxicity of Coumarin,” J. Pharmacol. Exptl. Therap., 118, 348 (1956). 28. A. Sporn, “Toxicity of Coumarin as a Flavoring Agent,” Igiena, 9, 121 (1960). 29. R. T. Williams, Detoxication Mechanisms, 2nd. ed., Wiley, New York (1959), p. 628. 30. M. R. Dodsworth, “Some Considerations on Sassafras Oil,” Bol. Divulgacio Inst. Oleos. No. 3, 21 (1945). 31. E. Guenther, The Essential Oils, Van Nostrand, New York (1950), Vol. 4, p. 280. 32. T. Naito, “The Constituents of the Volatile Oil from the Leaf of Cinnamomum camphora var. glaucescens,” J. Chem. Soc. Japan, 64, 1125 (1943). 33. F. B. Power and A. H. Solway, “The Constituents of the Essential Oil of Nutmeg,” J. Chem. Soc., 91, 2037 (1907). 34. T. Harada and Y. Saiki, “Pharmaceutical Studies of Japanese Wild Ginger. II. Paper Chromatography of Essential Oils,” Pharm. Bull. (Tokyo), 4, 223 (1956). 35. F. B. Power and F. H. Lees, “The Constituents of the Essential Oil of Cali- fornian Laurel,” J. Chem. Soc., 85, 629 (1904). 36. A. J. Lehman, “Report on Safrole,” Assoc. Food Drug Officials U.S., Quart. Bull., 25, 194 (1961). 37. R. T. Williams, Detoxication Mechanisms, 2nd ed., Wiley, New York (1959), p. 371. 38. P. Balavoine, “Thujone in Absinth and Its Imitations,” Mitt. Gebiete Lebensm. Hyg., 43, 195 (1952).

SPICES AND FLAVORS 173 39. 40. 41. 42. 43. 45. 47. 49. 51. 52. 33. F. H. Pike, M. Osnato, and J. Notkin, ‘““The Combined Action of Some Con- vulsant Agents in Small Doses and the Action of Bromides in Experimentally Induced Convulsions,” Arch. Neurol. Psychiat., 25, 1306 (1931). H. M. Keith and G. W. Stavraky, “‘Experimental Convulsions Induced by Administration of Thujone. A Pharmacologic Study of the Influence of the Autonomic Nervous System on These Convulsions,” Arch. Neurol. Psychiat., 34, 1022 (1935). L. Opper, ‘“‘Pathologic Picture of Thujone and Monobromated Camphor Convulsions: Comparison with Pathologic Picture of Human Epilepsy,” Arch. Neurol. Psychiat., 41, 460 (1939). M. I. Goryaev, I. M. Shabanov, and L. A. Ignatova, “Essential Oil of Artemisia mogoltavica,” Izv. Akad. Nauk Kaz. SSR, No. 123, Ser. Khim., No. 7, 75 (1953). M. I. Goryaev and Zh. K. Gimaddinov, “Essential Oil of Artemisia rutaefolia,” Zh. Prikl. Khim., 32, 1878 (1959). M. I. Goryaev and E. I. Satdarova, “Analysis of the Essential Oil of Artemisia serotina,” Tr. Inst. Khim. Nauk, Akad. Nauk Kaz. SSR, 4, 37 (1959). L. K. Tikhonova and M. I. Goryaev, “The Chemical Composition of the Essential Oil from Artemisia ferganensis,” Izv. Akad. Nauk Kaz. SSR, Ser. Khim., No. 2, 65 (1957). A. St. Pfau, “Composition of Commercial Oakmoss Products,” Riechstoffe ind. Kosmetik, 12, 179, 208 (1937). E. Jahns, “Uber das atherische Oel von Thuja occidentalis,” Arch. Pharm., 221, 748 (footnote) (1883). O. Wallach, “Zur Kenntniss der Terpene und der atherischen Oele,” Ann. Chem., 272, 99 (1893). N. Vernazza, “Thujone in Dalmation Sage Oil,” Acta Pharm. Jugoslav., 7, 163 (1957). C. H. Brieskorn and E. Wenger, “Constituents of Salvia officinalis. XI. The Analysis of Ethereal Sage Oil by Means of Gas and Thin-Layer Chromatog- raphy,” Arch. Pharm., 293, 21 (1960). H. Braun, “Effect of Extracts from Tanacetum vulgare on Gastric, Secretion,” Med. Monatsschr., 3, 528 (1949). Ya. Maizite, A. Klyava, and L. Kluga, ““Composition and Anthelmintic Action of Tansy,” Latvijas PSR Zinatnu Akad., Kim. Inst. Zinatniskie Raksti, 1, 101 (1950). R. E. Kremers, “The Chemistry of the Volatile Oil of Milfoil. A Study of the Application of Modern Organic Chemistry to Drug Plant Investigations,” J. Am. Pharm. Assoc., 10, 252 (1921); “Oil of Achillea millefolium, L. 1922,” J. Am. Pharm. Assoc., 14, 399 (1925). R. T. Williams, Detoxication Mechanisms, 2nd ed., Wiley, New York (1959), p. 530.

A. G. VAN VEEN Toxic Properties of Some Unusual Foods The author has avoided items that are dealt with in other parts of this volume, for example, fungal toxins, alkaloids, lathyrogens, cyanogens, saponins, and favism, and he has dealt with foods that are generally little known in the United States though common enough among certain groups of people. These are: quail, djenkol, kava-kava, Leu- caena glauca, bongkrek, and ackee. Quail Quail is a favorite game bird in southern Europe and along the North African coast, but it is little known that this bird is the subject of one of the oldest descriptions of food poisoning. After their flight from Egypt and during their wanderings through the desert, the Hebrews were twice saved from starvation by manna and by quail descending in huge numbers on their camp (Exodus, Numbers, Psalms).! The hungry people collected the birds and started to eat them. Numbers 11 especially mentions quail, and the story is repeated in Psalm 78. But “‘before they had sated their craving, while the food was still in their mouths, the anger of God rose against them, and He slew the strongest of them and laid low the picked men of Israel.” Apparently the Hebrews were punished for their greediness and over- eating; the fact that it is mentioned that they were punished with the “‘meat between their teeth,” gives the impression of a rather acute poisoning. In later centuries, numerous authors (Plinius the Elder, Lucretius, Galen, and Avicennus, for example) mention that quail can be poison- 174

SOME UNUSUAL FOODS 175 ous to men; and it was supposed that this might be because they some- times eat poison plants such as Helleborus and Conium maculatum. However, it has been only in recent times that this interesting and classic problem has been more thoroughly investigated. Sergent! describes signs and symptoms in a number of people in Algeria, who, during the last decennia, were reported to have become ill by the eating of so-called “‘green” quail (i.e., quail returning in spring from Central Africa to Europe and often quite emaciated). Nausea, vomiting, cold shivers, and partial slow-spreading paralysis are the main symptoms; usually the patients recover. In fall, the quail migrate from Europe over the Mediterranean to Africa; they are well fed and then do not seem to present any health hazard. Sergent was able to show that hemlock seed is practically harmless to quail, even in high dosage and in prolonged feeding tests, but very toxic when fed to dogs. He fed the meat of quail that had survived such feeding tests to two dogs, with fatal results. In general, the symptoms of the poisoning were the same as those described in human beings. Hemlock was a favored and effective poison in Socrates’ time and he himself was poisoned by it. Djenkol In certain parts of Indonesia, especially in Java and some parts of Sumatra, the population is fond of eating djenkol beans, the seeds of a leguminose tree, Pithecolobium lobatum Benth, which often grows very tall. In size and appearance the seeds resemble a horse chestnut and are brown in color. Another variety produces much smaller seeds that are black, flat, and compressed together in a relatively small pod. When maturing, and also after soaking, the beans develop a dis- agreeable odor, caused mainly by volatile sulfur compounds. By preference, the beans are consumed in this stage with the result that the consumer acquires the same disagreeable odor; however, this does not seem to bother him or his environment. It has been observed that consumers of djenkol beans often get acute kidney trouble, which results in anuria. The urine may contain red blood cells, epithelial cells, and sometimes clusters of white crystals (needles) that disappear upon standing (i.e., when the urine becomes alkaline). Sometimes these needles may clog the ureter, giving rise to such disturbances as necrosis or fistulae. In spite of these disagreeable side effects, which are observed rather often, the djenkol eaters will consume their beloved beans again the following season.

176 A. G. VAN VEEN It has been found that the djenkol bean contains a substance, djenkolic acid (I), often in a concentration of 1 to 2 percent.2 The CH —CHNHy —COOH S—CHp—CHNH> —COOH I ‘“‘black” variety of the bean from Sumatra may even contain 3 to 4 percent. This amino acid seems to occur in the bean in the free state and not to be bound to a protein or other high-molecular-weight compound.? It is, at least partly, absorbed from the intestinal tract and a part is excreted unaltered in the kidneys. If the urine has an alkaline pH, the djenkolic acid remains dissolved, but when it has a faintly acid reaction, the djenkolic acid crystallizes with the results mentioned above. It is interesting to note that the djenkol-eaters sometimes con- sume, either for preventive or curative purposes, the alkaline extract of some plant ashes. It has been shown that djenkolic acid can be metabolized by man and also by rabbits. It cannot replace cystine in the diet of white rats.2 Du Vigneaud and co-workers synthesized djenkolic acid in 1936 and improved the synthesis in 1947.4 Kava-kava (or Kawa-kawa) Piper methysticum, a weed between 2 and 5 feet high, easily grown in hot swampy areas, is well known in many islands in the Pacific. It is sometimes mentioned that a kind of black or green tea or beer is prepared from it. This drink, to which refreshing and tonic properties are often ascribed, is appreciated by some Westerners who have spent a long time in that part of the world. Sometimes, kava-kava is de- scribed or used as a drug having healing and even magic properties; as such, it has played an important role in the social and religious life on many Pacific islands. And sometimes it has been described as the source of a narcotic drug. In all cases, parts of the root and stem are used; sometimes, especially for “‘tea,”’ the leaves of the plant are also used. | It is not surprising that more than 75 years ago a monograph was written on this popular and somewhat mysterious plant.5 In his publi- cation, Lewin mentions that a water-insoluble resin that showed strong

SOME UNUSUAL FOODS 177 physiological action when injected in frogs and birds was extracted, but no details were given. From about 1914 to 1933, Borsche isolated a number of constituents from the resin, all derivatives of 6-styryl-2,4-pyronone. But in the thirteenth of a series of fourteen papers he stated that none of the substances he had isolated showed any action typical of kava-kava.§ Madaus’ has described some of the uses made of the kava-kava plant. The explanation of the different modes of action has been ascribed to the fact that if a simple aqueous extract is made from roots, stems, and/or leaves, the resulting liquid contains mainly water-soluble sub- stances with some essential oil and perhaps traces of resin. This liquid usually tastes slightly bitter and is in essence the famous kava-kava beer or tea, which seems to be harmless. If, however, the stem and root are chewed carefully, or ground intensively with saliva, lecithin, or some other emulsifying agent, the resulting emulsion, which is very bitter, shows an extremely fast action when given orally to rats, pigeons, monkeys, or humans. Often within 20 to 30 minutes the animals are in a deep sleep, which, in the case of monkeys, may last from 24 to 48 hours. This explains the use made of kava-kava by the Marindinese in the southern part of West New Guinea. Young children are given the roots and stems to chew; but they are not allowed to swallow the product. The resulting emulsion is filtered through grass into coconut shells and in the evening consumed by the adults in whom it causes a deep sound sleep during the night. Although the taste is extremely bitter, this potion can be consumed day after day, and, according to medical information, it does not seem to produce any harmful effects. It has been possible to isolate the causative substance in beautiful crystals called marindinine; however, after purification these appeared to be identical with one of the substances isolated by Borsche, i.e., dihydrokawain, which he stated to be without any pharmacological action. And indeed the water-insoluble crystals or powder do not show any effect when given to test animals. However, when these crystals were brought into a fine emulsion as described above, they showed the typical narcotic reaction within a short time.’ Leucaena glauca This is a shrub or low tree belonging to the leguminose family and is found in Central America, South America, and the Far East. It is used as a shade tree as well as for hedges in tea and coffee plantations. In

178 A. G. VAN VEEN certain tropical areas, the pods, seeds, and leaves of Leucaena glauca (Benth) are used as a food for human beings, but more often as an animal feed. There is no exact information about the areas in which Leucaena glauca is used in the human diet, but it is eaten more or less regularly in certain parts of Indonesia. It is an unusual food, as are the others so far described, in the sense that it is eaten by many people in certain areas, although they know that there is risk of certain undesirable side effects. The young leaves and small nods can be eaten raw; the mature small brown seeds can be roasted; leaves, pods, and seeds can be consumed in a soup together with other ingredients. At the end of the last century it was recorded in South America that sometimes animals (nonruminants) lost a part of their hair after eating parts of this shrub.? Around 1938, it was discovered in different parts of Indonesia during the course of food-consumption surveys that apparently healthy people in the villages were bald-headed and in possession of only a few new thin yellowish hairs. Typhoid, protein malnutrition, or other diseases could be excluded as causes of this condition. According to the local population, it was due to the con- sumption of parts of Leucaena glauca. Indeed, a small group of women and children were found about 48 hours after they had eaten leaves, pods, and seeds of the plant in a soup, and all had lost their hair within this period of time. They stated that scalp and eyebrows had been hurting somewhat, and at the time of the investigations scalp and eyebrows showed slight very localized edema.!0-11 Accordingly, experiments with animals (horses, pigs, and rats) were undertaken with rather inconsistent results. But fall-out of hair was one of the findings and there were indications that this was due to the amino acid ‘“‘mimosine” or “‘leucenine,”’ which occurs in the seed in concentrations of 1 to 4 percent, and is also found in the leaves and stems,10.11 Kostermans proposed two alternatives for the structural formula of this interesting product, which later was synthesized by Adams and Johnson.!2 The synthesis proved the structural formula to be 6-[N-(3- hydroxypyridone-4)]-a-aminopropionic acid. One of the interesting questions is that if mimosine is the active sub- stance, why are harmful results, such as fall-out of hair, so seldom seen among the population eating Leucaena glauca more or less regularly. In Japan and in Formosa some investigators undertook animal experiments and special mention should be made of the investigations of Jung-Yaw Lin and co-workers,!3 who showed that 1 percent mimo-

SOME UNUSUAL FOODS 179 sine in the diet is toxic for mice and rats. Rats show alopecia, retarded growth, and shortened life span. Mimosine forms an intensively red colored iron complex which is often observed when working with Leucaena glauca extracts and in the feces of Leucaena glauca consumers. Jung-Yaw Lin showed that this iron complex has little, if indeed any, toxicity. It is probable, therefore, that if meals containing Leucaena glauca are prepared in iron vessels, as is often the case, the product is harmless. They could also show that mimosine (in the same way as dopa, with which it has structurally much in common) condenses easily under physiological conditions with pyridoxal-5-phosphate and probably inactivates all enzymes con- taining this compound. This interesting observation may be the basis of the explanation of the pharmacological action of mimosine. Montagna showed that Leucaena glauca extracts cause gross damage to hair follicles of mice in the anagen stage.'4 The matrix of cells of the hair follicles was destroyed, and this continued until the eighth day when the follicles attained a stage similar to catagen. During the ingestion of the extract, the epidermis became very thin and atrophic, but it returned to normal when the animals were placed on a normal diet. Bongkrek Bongkrek, or tempeh bongkrek, is a product made from coconut press- cake or a similar coconut product (e.g., grated coconut) with the help of a fungus, usually Rhizopus oryzae. This is the same fungus that is used for the manufacture of better known products such as tempeh and ontjom, made from soybeans and from peanut presscake, respec- tively. Bongkrek is mainly eaten in central Java, a part of the country very rich in coconut palms. It consists of flat white cakes covered with a white mold, wrapped in banana or other large leaves. The fungus makes the product more digestible and attractive to eat. Although bongkrek is eaten by millions of people every day without harmful effects, occasionally groups of people do die or become seriously ill after consuming it even in small quantities. It has been found that especially when the product is not manufactured in the right way, a species of bacteria apparently present everywhere in that part of the country, gets the upper hand over the fungus after inoculation of the basic material, with usually fatal results for the consumers.!5 Especially in periods of economic depression, when there is no market for the locally produced oil and presscakes and unskilled villagers start to