Toxicants Occurring Naturally in Foods. (1966)

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Toxicants Occurring Naturally in Foods

Toxicants Occurring Naturally in Foods FOOD PROTECTION COMMITTEE FOOD AND NUTRITION BOARD NATIONAL ACADEMY OF SCIENCES NATIONAL RESEARCH COUNCIL PUBLICATION 1354 National Academy of Sciences National Research Council WASHINGTON, D.C. 1966

First printing, March 1967 Second printing, November 1967 Third printing, July 1971 Available from Printing and Publishing Office National Academy of Sciences 2101 Constitution Avenue Washington, D.C. 20418 Library of Congress Catalog Card Number: 66-60059

Preface The material in this monograph was prepared by individual scientists upon invitation of the Food Protection Committee of the Food and Nutrition Board and expresses their interpretations and conclusions. The Committee is indebted to each of the authors for his contribution to the monograph. Special thanks are owed Dr. Julius M. Coon, who was largely responsible for the organization and management of the project resulting in the monograph, and Dr. Justin L. Powers for valuable editorial assistance. FOOD PROTECTION COMMITTEE William J. Darby, Chairman David B. Hand, Vice Chairman John C. Ayres Paul R. Cannon Julius M. Coon Cyril L. Comar George C. Decker Kenneth P. DuBois Lloyd W. Hazleton James A. Miller Emil M. Mrak Bernard L. Oser R. Blackwell Smith, Jr. Henry F. Smyth, Jr.

Contents Introduction l Goitrogens in Foods 3 J. H. WILLS, JR. Estrogens in Foods 1g MARTIN STOB\, Tumorigenic and Carcinogenic Natural Products 24 JAMES A. MILLER Lathyrogens in Foods 40 IRWIN E. LIENER Favism~ 47 IRWIN E. LIENER Hemagglutinins in Foods 51 IRWIN E. LIENER Cyanogenetic Glycosides 58\, IRWIN BE. LIENER Some Naturally Occurring Stimulants and Depressants 62 - FRANK R. BLOOD ad GUILFORD G. RUDOLPH

Foods as Antigens and Allergens 72 HERBERT C. MANSMANN, JR. Pressor Amines in Foods 94 F. M. STRONG Antivitamins in Foodsv 98 SAMUEL LEPKOVSKY Naturally Occurring Antienzymes (Inhibitors)v 105 ANTHONY M. AMBROSE Natural Cholinesterase Inhibitors in Foods 112 DONALD G. CROSBY Natural Radioactivity in the Biosphere and Foodstuffs_ 117 C. L. COMAR , Fungal Toxins 126 BENJAMIN J. WILSON Seafood Toxins ~ 147 J. H. WILLS, JR. Toxicants Occurring Naturally in Spices and Flavors. 164 RICHARD L. HALL | Toxic Properties of Some Unusual Foods~- 174 A. G. VAN VEEN - Toxicity of the Vitamins _ 183 ROSEMARIE OSTWALD and GEORGE M. BRIGGS Excesses of Indispensable Amino Acids- 221 A. E. HARPER Toxicity of the Essential Minerals 229 GEORGE K. DAVIS Toxic Substances Present in Food Fats~ 236 JAMES F. MEAD and ROSLYN B. ALFIN-SLATER

Gossypol 242 EDWARD EAGLE Nitrates and Nitrites ~ 250 D. W. FASSETT Y Oxalates 257 D. W. FASSETTÂ¥ Toxic Effects of Dietary Sodium Chloride and ~ 267 the Protective Effect of Potassium GEORGE R. MENEELY~: Discussion 280 J. M. COON Contributors 287 Index 289

Introduction Public health activities associated with food regulation and control have long dealt with hazards of chance contamination of foods with pathogens and toxic substances. More recently, the toxic hazards associated with substances intentionally added to foods for some functional purpose or with residues of substances used in some phase of food production, processing, or storage have claimed attention. As a result of this orientation, the toxicology of added substances has received much study, and that of natural components of foods has received comparatively little. There is, nevertheless, a considerable literature on substances that occur naturally in foods that have, under some conditions, exhibited toxic properties. Some of the important and interesting aspects of this literature are reviewed here. Many plants and animals that man uses for food contain as natural constituents chemical substances known to have toxic properties. Others have produced toxic effects, but the substances responsible are unknown. In general, of course, man has learned to avoid dangerous exposure to the natural chemical components of his foods, but under some conditions the food may be more toxic than anticipated, or man may through ignorance or carelessness misuse the food. Thus, though acute poisoning is usually avoided, it is not invariably so. The public health significance associated with the naturally occurring toxicants in the food supply is to be sought primarily, however, in the realm of chronic toxicity. The material reviewed in this volume indicates a number of possible cause-and-effect relationships of this kind, but in the main can only point to the presence of a toxicant without evidence of any public health significance. This is true because in these cases 1

2 INTRODUCTION there has been no observation of adverse effect in man. This may be because intake is too small to cause effects or because chronic effects may be difficult to identify. Recognition of factors in the environment that may affect public health is basic to study of and eventual control of those factors. It is hoped that these reviews will contribute to the recognition of possible factors affecting public health, that they might stimulate additional study of our foods, and that they might attract the interest of toxi- cologists, plant geneticists, chemists, and others. The monograph is concerned mainly with products of “normal” metabolic or physiologic processes of plants and animals commonly or usually used as foods by man, including the uptake by plants of ele- ments and compounds from the soil and their translocation in the plants. In some instances, reviewers have included material that departs from the restriction of “commonly or usually used as foods by man,” but it has seemed useful to include such material to indicate the widespread occurrence of toxicants in nature. No attempt was made to discuss all such occurrences. A section on seafood poisons has been included because of the im- portance of these toxins even though some of the toxins discussed may not fit the category “‘products of normal processes.” In similar manner, the importance of new information about the toxins elaborated by molds commonly associated with foods justified the inclusion of the section on mycotoxins. Discussion of the great amount of diverse material available re- quired several approaches. There are a number of reviews in which the material is treated from the point of view of pharmacologic or physio- logic manifestations. Others approach the subject matter from the viewpoint of the foodstuffs responsible. Finally, a group of reviews deals with individual elements or compounds or with classes of related chemicals. Among these are discussions of toxic manifestations of some of the nutrients. It should perhaps be emphasized that it is not the purpose of this volume to discuss only those foods and toxic substances that have been associated with some manifestation of illness in man, but rather to present information, however ascertained, concerning the presence of naturally occurring toxic substances in man’s food. Much of the evidence is derived from observations in animals other than man and not because man has experienced any known harmful effects from con- suming the foods in question. Indeed, in many cases the evidence is only that a substance known to be toxic has been identified in a material used as food by man without any reference to intake levels.

J. H. WILLS, JR. Goitrogens in Foods At least four reviews have treated the naturally occurring goitrogens in foods.!— It is not intended to present here an exhaustive review of the field, but rather to give the principal facts about naturally occurring goitrogens in foods consumed by humans. Plants consumed only by animals will not be considered unless the goitrogenic principles they contain are transferred to milk, meat, or edible products derived from meat or milk, and, by their presence there, have a goitrogenic effect on the human consumers of foods. The earliest work suggesting that foods contain goitrogenic materials seems to have been that of Chesney and his co-workers*—’ and of Marine’s group’? showing that cabbage and other Brassicae contain a substance goitrogenic for the rabbit. Later, it was shown!® that seeds of the Brassicae tend to be more goitrogenic than the plants themselves. Indeed, the goitrogenic effects in man of edible portions of Brassicae, other than rutabaga and white turnip, are not regarded as firmly established.!! Of 61 foods examined for ability to decrease the rate of uptake of radioactive iodine by the thyroid of man, the most active was rutabaga; turnip, cabbage, peach, pear, strawberry, spinach, and carrot also had some activity in this regard.! 12 1 hiooxazolidone Derivatives It was not until 1949 that isolation and identification of a goitrogen in seeds of Brassicae and in the roots of turnip and rutabaga was re- ported.!!!3 The active substance was found to be /-5-vinyl-2-thio- oxazolidone, related to a previously identified naturally occurring 3

4 J. H. WILLS, JR. goitrogen in forage plants, 5 ,5-dimethyl-2-thiooxazolidone, isolated from hare’s ear mustard (Conringia orientalis)‘ and shown! to be goitrogenic. The seed containing the highest concentration of J-5-vinyl- 2-thiooxazolidone was that of kale, followed in order by seed of rutabaga, rape, broccoli, cabbage, kohlrabi, turnip, Brussels sprouts, and Chinese cabbage. The seeds of alyssum, candytuft, cauliflower, cress, honesty, mustard, radish, rock cress, and wallflower contained no /-5-vinyl-2-thiooxazolidone.!3 Astwood’s group found this deriva- tive of 2-thiooxazolidone to be a more potent goitrogen in man than propylthiouracil and to prevent the binding of iodine by the thyroid gland. Conversely, administration of iodine has been found to antago- nize in part the goitrogenic actions of cabbage and of Brassica seeds.!0.16 The epithelial hyperplasia within the thyroid gland that underlies the development of goiter has been found to be dependent on an increased secretion of thyrotrophin by the pituitary gland, because the thyroid atrophied invariably following hypophysectomy even though the goitrogenic influence was not removed.!720 One mode of action of J-5-vinyl-2-thiooxazolidone might be, therefore, that it stimulates secretion of thyrotrophin by the pituitary. That this actually is an important factor in goitrogenesis by this compound is indicated by the finding that administration of thyroxine to animals on a diet containing seeds of Brassicae completely antagonized the development of hyper- plasia of the thyroid gland.'6 Furthermore, Griesbach showed?! that hyperplasia of the thyroid in rats fed Brassica seeds was accompanied by an increase in the proportion of basophilic cells in the anterior pituitary and by the appearance of “‘signet cells’? there. Griesbach and Purves?° showed that the thyrotrophin concentration in the sera of rats fed Brassica seeds rose to about the same level as was found after thyroidectomy. The previously mentioned finding!® that administration of iodine, as either potassium iodide or diiodotyrosine, ameliorates, but does not prevent, epithelial hyperplasia within the thyroid gland of the rat fed seeds of Brassicae suggests that /-5-vinyl-2-thiooxazolidone does not prevent the binding of iodine by the thyroid gland.22 Further evidence for the correctness of this idea exists in the finding! that colloid re- appears within the thyroid of the rat on a diet containing rapeseed during involution of the hyperplastic gland following hypophysectomy, even though the rapeseed diet is continued. This goitrogen seems, therefore, to interfere to some extent with binding of iodine by the thyroid gland, because iodine is partially antagonistic to its hyper- plastic effect. In addition, it has an important goitrogenic action

GOITROGENS 5 through stimulation of secretion of thyrotrophin by the anterior pituitary. The active goitrogen, /-5-vinyl-2-thiooxazolidone, does not occur free in the seeds of Brassicae.'! The precursor in seeds of rutabaga and in roots of turnip and rutabaga has been identified tentatively as NaOS(O)20—C(SC6H110s)—=-NCH2CH(OH)CH==ChHz, from which the active oxazolidone is thought to be formed by enzyme action. This enzyme is destroyed by heating!!-23 or by exposure to strong alcohol."! Presumably, much of the variability evident in studies of the goitro- genicity of Brassicae in man is due to the fact that the foods were fed in raw or Only mildly heated form in some experiments and in a thoroughly cooked state in others. Attempts have been made to identify factors in the growing environ- ment of Brassicae that determine goitrogenicity. Sedlak24 grew cabbages on silica with nutrient solutions containing low or high concentrations of sulfate. Plants grown with the high concentration of sulfate con- tained higher concentrations of both inorganic and organic sulfur than those grown with the low concentrations, the difference being espe- cially striking for inorganic sulfur in leaves, and were strongly goitro- genic even though the plants from other seeds of the same lot grown under identical conditions, except for the sulfate concentration in the nutrient solution, failed to display any goitrogenic activity. The pre- viously mentioned suggestion?? about the nature of the precursor of J-5-vinyl-2-thiooxazolidone gives a basis for appreciating the importance of a supply of sulfur for the formation of the precursor, and ultimately of the potent goitrogen. Thiocyanates In a later paper, Langer et al. present evidence that the thiocyanate content may be an important factor in determining the goitrogenicity of cabbage. Langer, in a study of the epidemiology of goiter among nonsmokers in Poland,”6 found significant increases in the concentra- tion of thiocyanate in the blood serum at the end of spring and the beginning of summer and, again, at the end of autumn and the be- ginning of winter. These two peaks coincided with periods during which there was increased utilization of Brassicae as food. The role of thio- cyanate in the genesis of goiter from eating Brassicae is still somewhat unclear; it is possible that the goitrogenic activity of thiocyanate is that portion of the total goitrogenic activity of the Brassicae that can be antagonized by iodine. Research to be mentioned later in a more

6 J. H. WILLS, JR. specific manner has shown that iodine and thiocyanates are complete _mutual antagonists insofar as their effects on the thyroid gland are concerned. According to recent work by Sedlak,2’ the increase in the concentra- tion of thiocyanate in serum is only one facet of a fairly general increase in the concentrations of sulfur-containing compounds within the body when goitrogenic cabbage is fed. The concentration of thiocyanate (1.08 + 0.19 mg %) in the serum provided by such a diet is well below that of 8 to 10 mg % found?’ to induce enlargement of the thyroid in hypertensive patients treated with thiocyanates. It is possible, however, that a lower concentration of circulating thiocyanate may be significant when /-5-vinyl-2-thiooxazolidone also is present. Furthermore, the increased concentrations of other sulfur-containing compounds in the body when cabbage is fed may intensify the goitrogenic activity of the comparatively low circulating concentration of thiocyanate, both cystine and methionine having been found29 to have slight but demon- strable effects on oxygen consumption and on the size of the thyroid gland. In addition to the naturally occurring derivatives of 2-thiooxa- zolidone [the 5,5-dimethyl- from hare’s ear mustard (Conringia ori- entalis) and seeds of Cochlearia officinalis (watercress),>° the 5-phenyl- from seeds of Barbarea vulgaris (winter cress) and from seeds, leaves, stems, and roots of Reseda luteola (dyer’s weed),3! 32 and the 5-vinyl- from seeds and roots of some Brassicae'3], thiocyanates, liberated from a precursor glycoside in cabbage by a hydrolytic enzyme,! 33 are known to cause thyroid enlargement,>4 as previously discussed. Michajlovskij and Langer have presented estimates*5 of the concentrations of thio- cyanate present in a variety of plants; two plants commonly used in human diets having particularly high concentrations of thiocyanate are cauliflower and kale. We hasten to say that a daily intake of about 22 lb of cauliflower or kale would be required to furnish a goitrogenic concentration of thiocyanate in the blood. The thiocyanate from the fruit and leaves of Rapistrum rugosum (wild turnip) has been identified as y-methylsulfonylpropyl isothiocyanate and that from horseradish (Cochlearia armoracia) as butyl thiocyanate. A dose of 5 mg of the former compound has been found to reduce the uptake of 13!I by the thyroid of the rat. Transferability of Goitrogens The goitrogenic chemicals in cruciferous plants appear to be trans- ferable to the milk of cows consuming these plants and to be capable

GOITROGENS 7 of interfering with thyroid function of humans who drink such milk. Thus, Clements and Wishart>6 found that milk produced by cows fed on grass pasture had less effect on the uptake of 3!I by the thyroid gland than that produced by animals on diets in which 30 percent of the calories were supplied by kale, in which 25 percent of the calories were derived from such cruciferous weeds as lesser swine’s cress (Coronopus didymus), pepper cress (Lepidium ruderale), and shepherd’s purse (Capsella bursa pastoris); or in which about 20 percent of the calories came from turnips; or that produced by animals on pastures contami- nated heavily with wild turnip (Rapistrum rugosum). Similarly, Greene et al.37 found that milk from cows fed on pastures contaminated only lightly with cruciferous weeds but containing up to 40 percent of a moderately cyanogenic strain of clover was more goitrogenic than that from animals fed partially on kale. Clements in another study*® found that milk from cows fed on valley pastures heavily contaminated with wild turnip was goitrogenic, whereas milk from cows of the same region fed on ridge pastures, where wild turnip does not grow, was not goitrogenic. In a study of Finnish milks, Peltola39 concluded that plants of the Cruciferae, Compositae, and Umbelliferae families of the orders Papaverales, Campanulales, and Umbellales, respectively, are the probable sources of goitrogenic substances in milk from eastern Finland, where natural meadows are more common than in the western part of that country. Kreula and Kiesvaara‘*? have obtained evidence that the goitrogenic activity in milk is unlikely to be due to /-5-vinyl-2-thiooxazolidone even though turnip root or other forage known to provide this chemical is eaten by cows. This finding seems to indicate that the thiocyanate or some unknown goitrogenic material other than a derivative of 2-thio- oxazolidone must be ingested by cows grazed on grass having an admixture of goitrogenic weeds. There is some evidence that thio- cyanate may be the goitrogen in at least some places. Thus, Bobek and Pelczarska*! estimated the concentrations of thiocyanate present in milks and thyroid glands from cows from regions having different incidences of human goiter, concluding that the mean thiocyanate concentration within the thyroid glands of cows was correlated with the incidence of goiter in man more highly than was the concentration in the blood plasmas. Wright42 found that milk from goats fed on kale contained 4.6 mg % of thiocyanate although that from animals fed on grass pasture contained only 0.8 mg %. Langer and Michajlovskij reported*3 that rats, rabbits, and men fed kohlrabi gave evidence of absorption of thiocyanate by displaying either an elevated concentra- tion of thiocyanate in the blood (rabbit) or an increased excretion of

8 J. H. WILLS, JR. thiocyanate in the urine (rat and man). In a steady-state condition, the rat excreted unchanged in the urine about 80 percent of the thio- cyanate ingested per day. On the other hand, Peltola found in his study39 of the goitrogenic effect of Finnish milks that the goitrogenic activity of milk from Kuopio was not altered by the addition of approximately 10 times the normal amount of iodine to the diet. This finding renders somewhat suspect the conclusion that the goitrogen in milk from Kuopio is thiocyanate, because there is a great deal of evidence that thiocyanate and iodine are mutually completely antagonistic with respect to their effects on the thyroid gland.44-47 If the goitrogen in some milk is neither a thiocyanate nor a derivative of 2-thiooxazolidone, both the nature and the source of the goitrogen are unknown. Uncharacterized Goitrogens Besides the two important types of naturally occurring goitrogens mentioned previously, the ability to induce thyroid hyperplasia has been attributed to several substances or uncharacterized materials. As an example of the latter type of goitrogen, we can point to the unknown substance in liver found by Remington‘ to cause enlargement of the thyroid gland and by Hou*® to be extractable with alcohol. Clements and Wishart3¢ found that alcoholic extracts of lyophilized skimmed milk from cows fed either kale or pasturage contaminated with wild turnip also prevented the uptake of iodine by the thyroid. It is possible that these two alcohol-soluble goitrogens may be related or even identical. Another example of an uncharacterized goitrogen is the unknown substance in soybeans that seems to be capable of causing enlargement of the thyroid in experimental animals.5°5! This enlargement of the gland is associated with a marked decrease in the iodine content of the entire gland. Heating the soybean flour during processing reduced its goitrogenic effectiveness.52 The goitrogenic substance could not be removed from soybean flour by extraction with chloroform.*! A case of human goiter due apparently to a milk substitute made from soybeans has been reported by Ripp.*> There was in this case an obvious en- largement of the thyroid gland, without clear decrease in the metabolic rate. Removal of the soybean product from the diet after 15 months led to some decrease in the size of the gland but had no clear effect on the metabolic rate of the subject. The bulk effect discovered by Van Mid- dlesworth®3 and discussed later in this chapter may explain in part the

GOITROGENS 9 goitrogenic effect of soybeans. It is difficult to believe that this effect can be the sole explanation for the goitrogenicity of soybeans in view of the report by Halverson et al.5? that heating soybean flour during processing rendered it less goitrogenic. There is the possibility, however, that the heat treatment may have altered the digestibility of the soy- bean flour sufficiently to remove much of the bulking effect of the raw flour. OTHER POSSIBLE GOITROGENS Among other identified substances in foods to which some goitrogenic activity has been attributed are the noniodine halides and calcium, arsenic, cobalt, ergothionine, cyanoglycosides, and polysulfides. Noniodine Halides Although in general the noniodine halides are not directly goitrogenic, they do intensify the activity of known goitrogens,* fluorine having the greatest activity and chlorine the least. There are indications that areas of fluorosis in England and the Punjab of India, South Africa,56 and Soviet Asia’ tend to be coextensive with areas of endemic goiter. A high intake of calcium seems to intensify the harmful effects of fluo- rine,*6 the goitrogenicities of both fluorine and calcium being antago- nized by an increased intake of iodine.5658 When both fluorine and calcium are present in the diet in abnormal concentrations, more iodine is required to prevent hyperplasia of the glandular epithelium than when only one of these elements is present in the same greater-than-normal concentration. In apparent disagreement with the simple picture of mutual antago- nism between iodide and fluoride is the finding from Israel59 that where the iodine intake was sufficient the incidence of goiter was low, even though the fluorine concentrations of various waters varied from 0.3 to 0.9 ppm. The excess of the intake of iodine over the amount needed for maintenance may have been fairly large in this study, however. It is of interest that the authors report in the same paper that also in the rat iodine and fluorine are not antagonistic with respect to effects on the thyroid gland. We are left, therefore, with some question about the goitrogenic activity of fluorine, although the greater amount of the available evidence supports the attribution 'to this element of a hyper- plastic effect on the epithelium of the thyroid gland.

10 J. H. WILLS, JR. Metallic Elements Arsenic was found by Hesse® to limit the toxicity of both thyroxine and desiccated thyroid and to prevent death of animals poisoned just lethally with these materials. Coupling this experimental finding with the observation’! that the incidences of goiter, cretinism, and deaf- mutism are unusually high in the Styrian Alps, where arsenical ores have been used commonly as seasoning in place of onion or garlic in food, gave rise to the suspicion that arsenic may have a goitrogenic action. An experimental test of this hypothesis®? in which arsenic was added to the diet of rats to a concentration of 0.02 percent resulted in diminution of the rate of growth by 50 percent, diminution of the con- centration of iodine in the thyroid, and increase in the weight of the thyroid. The requirement of the animals for iodine was more than doubled; added iodide in the diet reduced both the toxicity and the goitrogenic activity of the arsenical diet. Cobalt and copper are other possible goitrogens among the metallic elements. Kolomiitseva has found® that the incidence of goiter is higher in regions containing higher concentrations of cobalt in soil and water, for example. Correspondingly, the concentrations of cobalt in potatoes and in pasture plants were also highest in the regions of comparatively high concentrations of cobalt in soil and water and of high incidence of goiter. In an earlier paper, the same author had re- ported® that in goiterous thyroids the ratio of In/Co, had a mean value of 71.2, whereas in normal thyroids the value was 162.5; the ratio of I,/Cu had mean values in goitrous and normal thyroids of 8.9 and 22.3, respectively. Ergothioneine Fairly active debate arose at one time over the claim that ergothioneine is a goitrogen. This claim seems to have been made first by Lawson and Rimington in 1947.65 Soon after the appearance of their paper, Astwood and Stanley reported® that this monothiol is inactive in man even in substantial doses. In an addendum to the paper of Astwood and Stanley, Lawson and Rimington® reiterated their claim of goitroge- nicity for ergothioneine and reported that in the rat daily subcu- taneously administered doses of 20 mg/kg of ergothioneine brought about an increase of the mean body weight from 152 to 163 g and an increase of the mean weight of the thyroid gland from 12 to 17.4 mg within 2 to 3 weeks. A biochemical study® showed that ergothioneine is

GOITROGENS 11 capable of inhibiting in vitro the conversion of acetyldiiodotyrosine to acetylthyroxine. Later, a rather careful restudy®? of the antithyroid activity of ergothioneine showed that it has no significant activity in vivo in the rat, the monkey, or man. When doses much larger than are likely to be met in a human diet are administered, some effect on thyroid function can be demonstrated. Cyanoglycosides Some mention has been made previously of the cyanoglucosides, which can yield thiocyanates as end products of the detoxication within the body of the cyano- derivatives formed by hydrolysis of the cyano- glycosides. Other types of glycosides in foods may interfere with func- tion of the thyroid gland. Thus, Moudgal and his co-workers at the University of Madras have shown70-7! that a glycoside isolated from the red skin covering such nuts as the peanut is goitrogenic not only because it interferes with uptake of inorganic iodide, as do the thio- cyanates, but also because it interferes with substitution of iodine into the tyrosine molecule, as do CO, CN-, 3-aminotriazol, azides, sulfides, thiourea, and thiouracil. Indolylacetonitrile In searching for new plant growth hormones, Henbest et al.’2 isolated from Brussels sprouts and cabbage a material active in promoting growth of avena coleoptiles. They identified this material as 3-indolyl- acetonitrile and synthesized the chemical. This plant hormone was shown by Jirousek?3 to be a fairly potent goitrogen in the rat, with a more rapid action than benzylcyanide. The same total dose of 3-indolyl- acetonitrile given to a rat (2 mg) had no effect in man. At about the same time, Jirousek reported” the isolation by chromatographic techniques of a strongly antithyroid preparation from varieties of Brassica oleracea. The preparation was found to consist of unidentified sulfhydryl compounds. One component of this polysulfide mixture has been identified partially ;75 it has a nucleus somewhat analogous to that of the derivatives of 2-thiooxazolidone discussed earlier: 1 ,2-diethia- cyclopentyl-4-ene-3-thione. This nucleus has substituting groups that have not been identified at positions 4 and 5. Evidence was presented that the group at position 5 may be a hydroxyphenyl-one or a trimethoxyphenyl-one.