Toxicants Occurring Naturally in Foods. (1966)

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264 D. W. FASSETT A second human study of the effect of spinach is that by Bonner et al.! Ten children, 5 to 8 years of age, were put on a control diet for 7 months prior to the beginning of the study. During the experimental periods, the children received the basal diet plus 100 g of canned spinach daily. This amount of spinach contained 0.7 g of oxalic acid and con- tributed 5 to 7 percent of the calcium of the basal diet. After a 25-day period on the basal diet, there was a 15-day period on the basal diet plus spinach, followed by a 5-day period in which oxalic acid and calcium equivalent to the amount in spinach were added to the basal diet. Nitrogen, calcium, and phosphorus were measured in the urine and feces. The results of this careful experiment showed no effect on the storage of any of the elements including calcium as a result of the spinach feedings. Although the results were variable in the oxalate— calcium portion of the feeding study, there was no significant deleterious effect. In general, the conclusion was reached that this very intensive treatment with spinach caused no obvious alteration in calcium metab- olism or balances in the children. Finally, an interesting study by Brune and Bredehorn? was carried out in the pig and was concerned with the ability of the pig to utilize some of the calcium from calcium oxalate added to the diet. Calcium oxalate (20 g) was added to the diet daily for 155 days. The diet was low in both calcium and oxalate. Suprisingly, 76 percent of the 20 g could not be accounted for in the feces. The assumption was made that bacterial degradation might have occurred in the intestine making the calcium available. There was also no increase in the oxalate in the urine, and no toxic symptoms were noted. Of even more significance, the authors gave calcium oxalate-'4C by mouth and noted the rapid appearance of carbon dioxide-!4C in expired air. Studies were also made with calcium oxalate containing**Ca. These studies indicated that 15 percent of the total calcium oxalate was degraded during its passage through the gastrointestinal tract. Balance studies indicated definite absorption of a considerable portion of calcium from calcium oxalate in this species. Considering the above experimental data in relation to modern under- standing of calcium metabolism and homeostasis, as well as the rela- tively low intake per day of the high oxalate-containing vegetables,29 the concern expressed by Kohman!2 regarding the possible hazardous effects of ingesting oxalate-containing vegetables seems unwarranted. The generally high calcium and vitamin D intake in the United States seems to provide further assurance that no deleterious effects are re- sulting from such sources. It would seem to require a rather improbable

OXALATES 265 combination of circumstances, a very high intake of oxalate-containing food plus a simultaneously low calcium and vitamin D intake over a prolonged period, for chronic toxic effects to be noted. REFERENCES 1. 10. 11. 12. 13. 15. 16. 17. 18. P. Bonner, F. C. Hummel, M. F. Bates, J. Horton, H. A. Hunscher, and I. G. Macy, “The Influence of a Daily Serving of Spinach or Its Equivalent in Oxalic Acid upon the Mineral Utilization of Children,” J. Pediat., 12, 188 (1938). H. Brune and H. Bredehorn, “On the Physiology of Bacterial Degradation of Calcium Oxalate and the Ability to Utilize Calcium from Calcium Oxalate in the Pig,” Z. Tierphysiol., Tiererndhr. Futtermittelk., 16, 214 1961; through Chem. Abstr., 56, 5190a (1962). G. M. Dack, Food Poisoning, University of Chicago Press, Chicago, Ill. (1943), pp. 55-56. E. B. Dewberry, Food Poisoning, Leonard Hill, Ltd., London (1959), pp. 188- 189, 245-246, and 248. R. H. Dreisbach, ed., Handbook of Poisoning: Diagnosis and Treatment, 3rd ed., Lange Medical Publications, Los Altos, Calif. (1961). V. A. Drill, ed., Pharmacology in Medicine, 2nd ed., McGraw-Hill, New York (1958). J. W. Fairbairn, ed., The Pharmacology of Plant Phenolics, Academic Press, London (1959). O. G. Fitzhugh and A. A. Nelson, ‘“‘The Comparative Chronic Toxicities of Fumaric, Tartaric, Oxalic and Maleic Acids,” J. Am. Pharm. Assoc. Sci. Ed., 36, 217 (1947). M. N. Gleason, R. E. Gosselin, and H. C. Hodge, eds., Clinical Toxicology of Commercial Products, Williams and Wilkins, Baltimore, Md. (1963). H. Jeghers and R. Murphy, ‘‘Practical Aspects of Oxalate Metabolism,” New Engl. J. Med., 233, 208 (1945). F. A. Johnston, T. J. McMillan, and G. D. Falconer, “‘Calcium Retained by Young Women Before and After Adding Spinach to the Diet,” J. Am. Dietet. Assoc., 28, 933 (1952). E. F. Kohman, “Oxalic Acid in Foods and Its Behavior and Fate in the Diet,” J. Nutr., 18, 233 (1939). S. Locket, Clinical Toxicology, Mosby, St. Louis, Mo. (1957). . C. G. MacKenzie and E. V. McCollum, ‘Some Effects of Dietary Oxalate on the Rat,” Am. J. Hyg., 25, 110 (1937). O. J. Malm, “‘Adaptation to Alterations in Calcium Intake,” in The Transfer of Calcium and Strontium Across Biological Membranes, R. H. Wasserman, ed., Academic Press, New York (1963), p. 143. G. Maue, “Uber die Inhaltsstoffe der Rhabarberblatter,” Z. Untersuch. Nahr. Genuss., 40, 345 (1920). K. F. Maxcy, in Preventive Medicine and Public Health, M. J. Rosenau, ed., Appleton-Century-Crofts, New York (1956), pp. 918-919. W. C. Muenscher, Poisonous Plants of the U.S., Macmillan, New York (1957), p. 67.

266 19, 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. D. W. FASSETT Anon., “‘Calcium Metabolism in Rats,” Nutr. Rev., 16, 148 (1958). R. Nicolaysen, N. Eeg-Larsen, and O. J. Malm, “Physiology of Calcium Metabolsim,” Physiol., Rev., 33, 424 (1953). J. J. Crotty, National Clearinghouse for Poison Control Centers, Washington, D.C., personal communication. H. F. Robb, ‘‘Death from Rhubarb Leaves Due to Oxalic Acid Poisoning,” J. Am. Med. Assoc., 73, 627 (1919). W. Schmid, ‘“‘Assay of Anthraglycoside Drugs. Use of the Leaves of Medicinal and Edible Rhubarb,” Deut. Apotheker-Ztg., 91, 452 (1951). T. Sollmann, A Manual of Pharmacology and Its Applications to Therapeutics and Toxicology, 8th ed., Saunders, Philadelphia, Pa. (1957). W. S. Spector, ed., Handbook of Biological Data, Saunders, Philadelphia, Pa. (1956), p. 196. E. von Streicher, ““Akutes Nierenversagen und Ikterus nach einer Vergiftung mit Rhabarberblattern,” Deut. Med. Wochschr., 89, 2379 (1964). H. Tallqvist and I. Vaananen, “Death of a Child from Oxalic Acid Poisoning Due to Eating Rhubarb Leaves,” Ann. Paediat. Fenniae, 6, 144 (1960). F. W. Tanner and L. P. Tanner, Food Borne Infections and Intoxications, 2nd ed., Garrard Press, Champaign, Ill. (1953), pp. 157-160. U.S. Department of Agriculture, Food Consumption of Households in the United States, Household Food Consumption Survey 1955, Report No. 1, Washington, D.C. (1956). R. H. Wasserman, ed., The Transfer of Calcium and Strontium Across Biological Membranes, Academic Press, New York (1963). J. M. Watt and M. G. Breyer-Brandwijk, The Medicinal and Poisonous Plants of Southern and Eastern Africa, 2nd ed., Livingstone, Edinburgh and London (1962). C. Wehmer, Die Pflanzenstoffe, Vol. 1, Gustav Fischer, Jena (1929).

GEORGE R. MENEELY Toxic Effects of Dietary Sodium Chloride and the Protective Effect of Potassium Sodium chloride is naturally present in nearly all living things and, therefore, has always been a component of food. By the beginning of recorded history, the human use of extra sodium chloride added to the diet as a condiment was well established. How it came to be so is entirely speculative. There is some evidence that use of salt is habit forming in the same sense that tobacco is, but there certainly is no doubt that people accustomed to its use have fought wars to possess a source of it, and numberless men have risked death to smuggle it. There are parts of the ancient world where superficial excrescences of it occur naturally, and the process of obtaining it by evaporation of saline waters is only a procedure copied by man from nature in areas where it occurs spontaneously on the shores of dead seas. The anti- septic properties of brine must have been noticed early by man. The use of salt to preserve foods that otherwise would decay seems a reasonable pathway whereby early man may have developed his taste for it. The elemental composition of sodium chloride was learned at the turn of the nineteenth century. Scheele discovered chlorine in 1774 but thought it contained oxygen. Davy named it in 1810, recognizing that it was an element. He had isolated sodium by electrolysis in 1807. By the middle of the nineteenth century, there were reports of disturbances of sodium balance in disease states, especially in cholera in which depletion of sodium is a striking feature. Physiologists were fascinated by sodium chloride in the latter half of the nineteenth century, and extensive speculations on the relation of the salt content of the her- bivorous diet compared with the diet of the carnivores led to the 267

268 GEORGE R. MENEELY theory, attributed to von Bunge, that herbivorous animals are com- pelled to go to salt licks to obtain extra sodium chloride to balance the high intake of potassium characteristic of herbivorous diet. It had been established by 1840 that the sodium chloride content of the natural herbivorous and carnivorous diets is the same and that the difference lies in the much higher potassium of the former. This established the error of the earlier theory that herbivores got their salt from salt licks and the carnivores got theirs from the herbivores. The concept that sodium chloride is required to protect against high dietary potassium seems quite fallacious now. Indeed, the reverse is probably the case. As will be seen in the discussion of potassium in the diet, there is good animal and human experimental evidence that extra potassium exerts a protective effect on the toxic effects of excess sodium chloride ingestion. Sodium is widespread in nature. It is the most abundant of the alkali elements and the seventh element in amount in the crust of the earth. It is highly reactive and never found free. In living organisms, it occurs in manifold combinations, and it is erroneous to think of it as occurring always as the chloride, although frequently it is so expressed in chemical analyses. Sodium enters the body in five ways: first, there is sodium in nearly all drinking water, quite a lot in certain areas, and, where water softeners are used, two atoms of sodium are added for every atom of calcium or magnesium exchanged. If the water supply contains as much as 25 mg of sodium per 100 ml, and if an intake of water in food and drink is taken to be 2 liters, the sodium intake will be as high as 500 mg per day. In Galveston, Texas, the municipal water supply contains 34 mg per 100 ml, and in Crandal, Texas, it contains 170 mg per 100 ml. The latter is rarely drunk but it is used for cooking. The high sodium content of Galveston drinking water is well known to the medical pro- fession as a problem in patients with congestive heart failure. Second, sodium occurs naturally in all foods, although in many the content is very low; for example, fresh peas contain only 0.9 mg of sodium per 100 g. The third pathway is via food processing, and a great deal of sodium, usually in the form of sodium chloride, may be added. For example, canned peas, even with the liquor poured off, contain 230 mg of sodium per 100 g. Expressed as sodium chloride this is 580 mg. Even the con- ventional freezing process uses sodium chloride so that frozen peas contain 100 mg per 100 g. A point worth noting (see also the discussion of potassium) is that, at the same time the sodium 1s added, the potas- sium is depleted. Fresh peas contain 380 mg of potassium per 100 g,

SODIUM CHLORIDE 269 while in canned peas drained of the liquor the potassium is reduced to 180 mg, and in frozen peas it is reduced to 160 mg. The fourth pathway is addition of salt in the cooking process within the home. It is highly variable from household to household, as is the matter of the disposition of the cooking water. It appears probable that the old custom of saving all or almost all cooking waters as pot-au-feu or pot liquor is vanishing in the United States. Generally, in the prepa- ration of vegetables, salted water is brought to a boil and raw or frozen vegetables added. At the end of the cooking period, the vege- tables are drained, the cooking water being discarded. The net effect is a further addition of sodium and a further depletion of potassium. The fifth pathway is addition of common salt to food at the table. Again there is great individual variation, dependent, apparently, upon individual taste for salt. Dahl observed that patients on diets containing up to 250 mg of salt per day immediately noticed the addition of 1 g per day, whereas among subject eating 10 to 20 g per day the addition of 5 or even 10 g would go unnoticed. On the other hand, Dahl found it easy to alter individual taste for salt, much easier than for some other well- recognized tastes. There are only a limited number of studies on the human require- ment for sodium. It has long been recognized as essential to life. Esti- mates of daily requirement have ranged as high as 15 g (as sodium chloride) per day, but clearly 5 g is ample and 1 g per day is more probably correct. Many studies have shown that humans with normal kidney function maintain salt balance easily on daily intakes below | g. That sodium chloride might have harmful effects if eaten in excess was suspected long before any objective evidence on the subject existed. Widespread use and familiarity with salt led most, however, to the assumption that it was a harmless substance. The earliest association of salt with human hypertension is thought by Chapman, in the Bell Sym- posium, to be the work of Ambard and Beaujard in 1904. Benefit in a disease state by restriction of an element in the diet does not, of course, establish it as having a causal relation to the disease. Therapeutic re- striction of salt fell in and out of favor throughout the first four decades of this century, but the merit of salt restriction in controlling edema in congestive heart failure was certainly firmly established by the fourth decade. The association with hypertension proved more subtle. The effect of salt restriction in human hypertension, however, is now very well documented. In general, patients so treated fall into one of three categories: some experience a return of the blood pressure to normal levels, some experience a reduction in blood pressure but not to normal,

270 GEORGE R. MENEBLY and some show no fall in blood pressure at all. Again, speaking gen- erally, the longer the duration of the hypertension and the more severe its manifestations, the less likely is a completely favorable response. The success of the natriuretic agents in controlling hypertension further documents the association of human hypertension and dietary sodium chloride. It has not proved easy to demonstrate a causal relation between sodium chloride intake and human hypertension. Suspicion of such a re- lationship was strong by 1951 when Braun-Menendez, commented, at the Bell Symposium in Minneapolis, that, whatever the experimental method for producing hypertension, increased salt intake facilitated its obtainment and salt restriction prevented it. Selye, Hall, and Rowley and Knowlton, Loeb, Stoerk, and Seegal found hypertension produced by desoxycorticosterone acetate with the addition of extra sodium chloride. With hypertonic saline as the sole source of liquid, Lenel, Katz, and Rodbard produced hypertension in the chicken; Sapirstein, Brandt, and Drury in the rat; and Fukuda in the rabbit. In 1951, the author and his colleagues began experiments that showed that chronic ingestion of excess sodium chloride as the sole variable in an otherwise wholesome diet reliably produced hypertension in the rat that appeared to duplicate human hypertension clinically and morpho- logically. Various levels of sodium chloride were investigated, but attention focused finally on three ranges as most revealing and most realistically related to the human problem. The first range, the ‘“‘control’’ level, is from 0.15 to 2.0 percent. Over this range only minor differences in growth rate were found, and animals eating such diets never became hypertensive. The second range of interest is 2.8 to 5.6 percent, which represents a moderate excess of sodium chloride. Finally, 7.0 to 9.8 percent sodium chloride in the diet represented a high level of excess salt. It may seem that these levels are out of the range of human con- sumption, but this is not the case. These levels may be compared on a percentage of nutriment basis: 2.8 percent sodium chloride in the purified rat diet corresponds to 14 g of sodium chloride daily in an ordinary diet for man. The equivalent human intake in grams per day may be obtained by multiplying the rat diet percent composition by 5. Thus the control (0.15 to 2.0 percent) level corresponded roughly to 0.75 to 10 g of NaCl daily for man. The “moderate” excess range (2.8 to 5.6 percent) corresponded to 14 to 28 g per day and was frankly hypertensigenic and life-shortening. Finally, the “high” level of excess salt (7.0 to 9.8 percent), equivalent to 35 to 49 g daily, has its counter-

SODIUM CHLORIDE 271 part in man in only a few parts of the world, most notably northern Japan. It was drastically hypertensigenic in the rat and it is drastically hypertensigenic in the Japanese. At all levels of salt feeding the rats evidenced growth and good de- velopment, but at levels above the control there were successive decre- ments in growth. These persisted throughout the life of the animal. The water consumption (and urine production) was proportional to the dietary sodium chloride content. This association of water drinking, urine formation, and salt intake is well known, the earliest observation being recorded in Pliny’s Natural History. It was, for example, com- mented on by Thoreau who wrote in Walden: ‘‘Finally, as for salt, that grossest of groceries . . . if I did without it altogether, I should probably drink the less water.” Consistent and reproducible blood pressure observations were obtained in early experiments about the ninth month, at which time hypertension was well established in animals eating above the control levels of salt. It is of considerable interest to note that, although the ‘mean blood pressure of each group was successively higher and es- sentially proportional to the sodium chloride content of the diet, there was a very considerable scatter of individual values. The mean systolic blood pressure at control levels of salt was approximately 122 mm Hg. At the lower level of excess salt feeding (2.8 percent) the mean of the systolic blood pressures had risen to about 130. Yet there were indi- viduals in this group who had pressures as high as 160 mm Hg and others as low as 114. By the same token, at a high level of salt feeding (9.8 percent), the mean systolic blood pressure for the whole group of animals had risen to 152 mm Hg, but there were rats with pressures as high as 205 and one rat with a pressure of only 125. It is further of con- siderable interest that those animals lying significantly above or sig- nificantly below the means of their group tended to maintain this relative position throughout life. Thus, it is evident that even in fairly homogenous experimental material such as the male Sprague-Dawley rat there are substantial differences in susceptibility to hypertension induced by this means. One could reliably predict that those animals that had the higher levels of hypertension for their group were the more likely to show severe electrocardiographic changes later in life and also to show serum cholesterol elevation. Conversely, those that had the lower pressures were the less likely to evidence severe electrocardio- graphic changes and less likely to manifest abnormally high cholesterol. The time relations of the blood pressure change was such that at high levels of excess salt feeding the blood pressure rose rapidly to high

272 GEORGE R. MENEELY levels, while at lower levels of excess salt feeding the blood pressure rose less rapidly to intermediate hypertensive levels. Among the hypertensive animals, specific abnormalities of the elec- trocardiagram were observed which were closely similar to those seen in humans with hypertension, namely, a high incidence of T wave abnormalities, S-T segment abnormalities, left axis deviation, left ventricular strain pattern, and prolonged duration of the QRS com- plex. On the other hand, arrhythmia and P-R interval abnormalities occurred only in low incidence. Serum cholesterol levels tended to increase with increasing dietary sodium chloride. There was a strong positive correlation between serum cholesterol and the observed level of the blood pressure. Perhaps the most sensitive index of the adverse effects of sodium chloride upon these rats was the survival data. No significant difference in survival was seen between control animals and those eating the lower levels of high salt (2.8 to 5.6 percent) until the seventeenth month of the experiment. For human beings, this would correspond roughly to age 51 if 10 days for a rat is equivalent to a year for man. Thereafter the difference increased. The median duration of life for rats eating 5.6 percent sodium chloride was many months less than that of controls. In the case of the higher levels of high salt feeding, for example, 8.4 percent, there was an 8-month difference between the median duration of survival in the high-salt rats and the controls. If one were to translate this figure to man, this would be equivalent to a difference in the median duration of life of about 32 years. Repeated experiments have shown that the slopes of the survival curves were associated with the level of dietary salt and were identical in comparable experiments. One experiment of especial interest was performed on a small num- ber of elderly rats made available through the courtesy of Dr. Kenneth Kohlstaadt of Eli Lilly and Company. This colony of 26 male rats, nearly 2 years in age, had been maintained previously on a chow diet. When placed on test diets containing 5.6 and 9.8 percent sodium chloride, they gradually become hypertensive, but it is important to note that the levels of elevated blood pressure attained were always less than was the case with young rats who ate the same ration for the same length of time. While sodium chloride did indeed have a hyper- tensigenic effect when started late in life, the effect was not nearly so great as when started early in life. In young female rates fed corresponding levels of increased sodium chloride, the level of blood pressure obtained was never as high as that for the male rats.

SODIUM CHLORIDE 273 Each animal that died was autopsied, the organs were weighed and tissue sections obtained for microscopic examination. The weight of the kidneys and the weight of the heart increased in proportion to the sodium chloride in the diet and, of course, to the level of blood pressure which was also proportional to the salt in the diet. The findings in the adrenals were less consistent: at high levels of salt feeding there was a significant increase in adrenal weight but the variability was con- siderable and there was only a general trend for the adrenals to increase in weight as sodium chloride increased. The characteristic alteration noted in the microscopic examination of the tissues among animals with severe hypertension was a diffuse disease involving especially the arterioles and small arteries. In the kidney, this was manifest by rela- tively bloodless enlarged glomeruli with swelling and vacuolation of both endothelium and epithelium and large amounts of sudanophilic lipid. The tubules were dilated and the epithelium was hyperplastic and swollen with lipid and hyaline droplets. The small arteries and arterioles showed fatty degeneration of muscle cells and often underwent smudgy eosinophilic necrosis. Similar arteriolar lesions were found in other viscera, most particularly the pancreas and the testes. The late Dr. Ernest Goodpasture examined the tissues of all of the rats from Experi- ment I and drew particular attention to the apparent similarity be- tween the morphological lesion seen at the high levels of high salt feeding and that seen in human malignant hypertension. He further found that when arteriolar lesions were prominent in the kidneys they were also always present in the testes. Since the testes of rats are readily available for biopsy, this suggested to him the possibility that one might follow serially the development of the morphological lesion. In rats that exhibited the clinical course of benign essential hyper- tension, there was a lack of striking anatomical alteration in the microscopic sections, as is true with humans. In fact, with ordinary hematoxylin and eosin stains, the several pathologists who examined these tissues were unable to find any consistent differences between these animals and the controls. It is worthwhile to examine why the picture of chronic sodium chlo- ride toxicity is so clear in animal experimental work and so blurry in human studies. Dahl has assembled an impressive body of evidence by examining the salt intake in different populations. The association of hypertension and salt intake is overwhelming. In contrast, studies within populations have largely been unconvincing. There are several factors that probably account for this latter finding. In any given region there tends to be an average level of salt intake with considerable

274 GEORGE R. MENBELY variation about this mean but, in most instances, not a sufficient spread among a sufficient number of individuals to reveal the hypertensigenic salt effect in the presence of other variables. Of these, the most notable is the probable role of heredity, which we will discuss more below, but also, there are a number of ways of acquiring hypertension, especially in association with diseases of the kidney. In one investigation in Nashville, Tennessee (unpublished), some 3,000 individuals were queried concerning salt intake and blood pressure was measured. Three findings germane to the thesis of this report emerged. First, the distribution of observed blood pressures was not wide, due, it was thought, to the youth of the population studied (potential military draftees). Further, when hypertension was found in this group, it was almost always possible to elicit a history of kidney disease from the individual manifesting it. Finally, from a random sample of 24-hour urine collections it was abundantly apparent that there was no correla- tion between the amount of salt these individuals thought they were eating and the amount actually consumed. Another field study of a local population by this author and his colleagues gave equally inde- terminate results. It is evident that a local population with a relatively low mobility comes to consume about the same amount of salt by reason of common local custom and identical sources of food. There will always be a few individuals distributed well away from the mean but apparently not enough to bring out the hypertensigenic salt effect from among the other variables. On the other hand, as Dahl has so clearly shown, when different populations with widely differing salt- eating habits are investigated, the effect is abundantly evident. It has long been known that there was a familial factor in hyper- tension, although it has not been clear whether the higher incidence of hypertension among the offspring of hypertensives was purely heredi- tary or in some way acquired in childhood. The reports of Brest and Moyer, of Schroeder, of Thomas, of Platt, of Pickering, and of many others in this connection are well known. It now appears that Dahl has resolved the problem. He interbred rats that developed high hyper- tension on increased salt intake and also interbred those that developed little or no elevation of blood pressure on high salt diets. By repeating this procedure, it proved possible to develop two distinct strains of rats, one extremely sensitive to increased salt intake and the other extremely resistant to it. It thus appears reasonable to believe that the toxic effect of chronic excess sodium chloride eating in man is con- ditional and depends upon his hereditary material. Given the appro- priate hereditary proclivity and given a salt intake in excess of normal requirement, the result will be hypertension.

SODIUM CHLORIDE 275 Throughout nature, potassium is the principal intracellular cation. It therefore is present in all foods. There have been parts of the world where potassium salts have been used as a condiment. Lapicque found natives of Africa extracting the ash of certain plants (lixiviation) to make a condiment used somewhat like common salt. Many potassium salts, however, have a bitter disagreeable taste (salt of wormwood = po- tassium carbonate) and its use as a condiment has never been wide- spread. It is extremely difficult to make an animal (or a normal human being) potassium deficient since potassium is so widespread in nature, and there is no evidence that normal man or animals ever eat an ex- cessive amount of it. In disease states in man, however, excess and deficiency conditions of potassium exist. The former are usually associated with impaired renal formation. One cannot increase total body potassium in normal subjects by feeding extra potassium, as the author and his colleagues found some years ago. On the other hand, in kidney disease, serious states of potassium intoxication occur frequently as a clinical problem. Hyperkalemia, excessive potassium in the blood, may occur, but the electrocardiogram is a more sensitive indicator, both of excess and of deficit. There is about 20 times as much potassium in the cellular fluid as in the extracellular, and the electrocardiogram reflects changed intracellular energetics due to potassium deficit or excess before changes in plasma potassium level are detectable. Potas- sium deficiency occurs as a clinical problem most usually as an tatro- genic disorder following administration of diuretics or the mineral- acorticoid steroids. Alimentary tract loss in mucus colitis and certain rare tumors, and renal loss in certain uncommon renal disorders also can induce potassium deficit. While exogenous hyperkalemic states are hard to induce, and probably impossible by mouth in the presence of normal kidneys, endogenous hyperkalemia readily occurs among individuals with borderline kidney function when disease or crushing injury destroys large numbers of cells, releasing the high concentration of intracellular potassium into the extracellular compartment from which a moderately impaired kidney may be unable to drain it rapidly enough to avoid potassium intoxication. In animal experiments, it is easy to demonstrate a protective action of extra potassium against the toxic effects of chronic excessive dietary sodium chloride. The addition of extra potassium chloride to rat diets high in sodium chloride increased the median duration of life by 7 or 8 months. The concurrent blood pressure observations were of special interest. As previously stated, at moderate levels of excess salt feeding a moderate hypertension developed. When extra potassium chloride was added to a diet containing 5.6 percent sodium chloride there was no

276 GEORGE R. MENEELY change in the hypertensigenic action of the extra sodium chloride, but there was a tremendous improvement in survival. The median duration of life was increased by 7 months, and yet throughout life the blood pressure persisted at intermediate levels, just as in animals who re- ceived no extra potassium. In contrast to this, at levels of excess salt feeding, which ordinarily produced high levels of hypertension, the extra potassium chloride had the effect of ameliorating the hypertensi- genic action of sodium chloride so that only moderate hypertension developed. Again, a dramatic increase in the median duration of life of approximately 8 months was observed. It was evident from these data that there were at least two kinds of hypertension in the animals eating excessive amounts of salt. The first, a moderate hypertension from moderate levels of excess salt feeding, which was not significantly altered by the addition of extra potassium chloride; and the second, a high hypertension associated with high levels of extra salt feeding, which was held to intermediate levels by the addition of extra potassium chloride. It was probably significant that the total body sodium of the moderate salt-eating animals was essen- tially the same as that of controls, whereas in animals eating high levels of excess sodium chloride there was a significant increase in total body sodium. Further, upon the addition of potassium chloride to each of these diets, no significant effect upon total body sodium was observed at moderate levels of sodium chloride increase, whereas at high levels of sodium chloride feeding with extra potassium the total body sodium stayed within normal limits. The above observations shed light upon the puzzling situation with regard to human beings and dietary sodium and potassium. It is evident that there were five quite different categories of rats, and there should probably be at least five corresponding categories of man. First, there were those with optimal sodium and potassium intake who lived a long life and did not develop hypertension. Second, there were those with moderately increased sodium intake and normal potassium intake. These animals developed a moderate hypertension and exhibited a shortened life span, but did not have any significant alteration in total body sodium content. Third, there were those with moderately excessive sodium intake and extra potassium intake. These animals were dis- tinguishable from the second category only in that they survived significantly longer. Fourth, there were those with a highly excessive sodium chloride intake and a normal potassium intake. These animals developed a severe hypertension, their life span was greatly shortened, and their total body sodium was significantly elevated. In the fifth

SODIUM CHLORIDE 277 category were those rats with a highly excessive sodium chloride intake and an increased potassium intake. This group was characterized by the development of a moderate hypertension, a substantial prolongation of life when compared with animals eating the same amount of sodium chloride but without the supplemental potassium chloride, and a total body sodium that remained within normal limits. If these data were transferable directly to man, it would account for the fact that some hypertensive patients exhibit a fall in blood pressure when extra potassium chloride is provided and others do not. One could hardly expect potassium to produce a fall in blood pressure unless the individual (a) had a hypertension corresponding to the high salt intake hypertension of the rat and (b) was not already receiving a sufficient amount of potassium. Further, the benefit of extra potassium fed to an individual eating an intermediate level of high salt could be detected, so far as one is able to determine, only by observing a pro- longation of life. This is obviously impossible in the individual. The protective effect of extra potassium in diets high in sodium chloride has been confirmed in animals by Dahl. Some most interesting human studies by Sasaki confirm the effect in man. BIBLIOGRAPHY L. Ambard and E. Beaujard, ‘“‘Causes de l’hypertension arterielle,”” Arch. Gen. Med. 1, 520 (1904). C. O. T. Ball and G. R. Meneely, “‘Observations on Dietary Sodium Chloride,” J. Am. Dietet. Assoc., 33, 366 (1957). . E. T. Bell, ed., Hypertension. A Symposium, University of Minnesota Press, Min- neapolis (1951). A. N. Brest and J. H. Moyer, ““The Etiology and Therapy of Essential Hypertension. A Review,” J. S. Carolina Med. Assoc., 56, 171 (1960). G. von Bunge, Lehrbuch der physiologischen und pathologischen Chemie (3rd ed., Verlag von F. C. W. Vogel, Leipzig (1894). L. K. Dahl and R. A. Love, “Evidence for Relationship between Sodium (Chloride) Intake and Human Essential Hypertension,” A.M.A. Arch. Internal Med., 94, 525 (1954). L. K. Dahl and R. A. Love, “Etiological Role of Sodium Chloride Intake in Essential Hypertension in Humans,” J. Am. Med. Assoc., 164, 397 (1957). L. K. Dahl, “Medical Progress. Salt Intake and Salt Need,” New Engl. J. Med., 258, 1152, 1205 (1958). L. K. Dahl, Possible Role of Salt Intake in Development of Essential Hypertension. Essential Hypertension, An International Symposium, Springer Verlag, Heidelberg (1960). L. K. Dahl, L. Silver, R. W. Christie, and J. Genest, “‘Adrenocortical Function after Prolonged Salt Restriction in Hypertension,” Nature, 185, 110 (1960).

278 GEORGE R. MENEBLY L. K. Dahl, M. Heine, and L. Tassinari, “Effects of Chronic Excess Salt Ingestion. Evidence that Genetic Factors Play an Important Role in Susceptibility to Experi- mental Hypertension,” J. Exptl. Med., 115, 1173 (1962). L. K. Dahl and E. Schackow, “Effects of Chronic Excess Salt Ingestion: Experi- mental Hypertension in the Rat,”’ Can. Med. Assoc. J., 90, 155 (1964). L. K. Dahl, “‘Studies on the Role of Salt and Gene‘ics in Hypertension,” Acad. Med. N. J. Bull., 10, 269 (1964). L. K. Dahl, M. Heine, and L. Tassinari, “Effects of Chronic Excess Salt Inges- tion. Vascular Reactivity in Two Strains of Rats with Opposite Genetics Susceptibility to Experimental Hypertension,” Supp. II Circulation, 29 and 30, 11 (1964). L. K. Dahl, M. Heine, and L. Tassinari, ‘Effects of Chronic Excess Salt Ingestion. Further Demonstration that Genetic Factors Influence the Development of Hypertension: Evidence from Experimental Hypertension Due to Cortisone and to Adrenal Regeneration,” J. Exptl. Med., 122, 533 (1965). G. L. Eskew, Salt, the Fifth Element, J. G. Ferguson and Associates, Chicago, Il. (1948). T. Fukuda, “L’hypertension par le sel chez les lapins et ses relations avec la glande surrenale,”” Union Med. Canada, 80, 1278 (1951). A. R. Holmberg, Nomads of the Long Bow: The Siriono of Eastern Boliva, Smiths- onian Institution, Institute of Social Anthropology, Publication No. 10, U.S. Govt. Printing Office, Washington, D.C. (1950), p. 35. E. Hughes, Studies in Administration and Finance, University of Manchester Press, Manchester (1934). E. Jones, Essays in Applied Psycho-analysis, Vol. 2, Hogarth Press, London (1951). H. Kaunitz, “Causes and Consequences of Salt Consumption,” Nature, 178, 1141 (1956). S. Kaneta, K. Ishiguro, S. Kobayashi, and E. Takahashi, “An Epidemiological Study on Nutrition and Cerebrovascular Lesions in Tohoku Area of Japan,” Tohoku J. Exptl. Med., 83, 398 (1964). A. I. Knowlton, E. N. Loeb, H. C. Stoerk, and B. C. Seegal, ‘“‘Desoxycorticosterone Acetate: Potentiation of Its Activity by Sodium Chloride,” J. Exptl. Med., 85, 187 (1947). L. Lapicque, ‘“Documents ethnographiques sur |’alimentation minerale,” Anthro- pologie, 7, 35 (1896). R. Lenel, L. N. Katz, and S. Rodbard, “‘Arterial Hypertension in Chicken,” Am. J. Physiol., 152, 557 (1948). G. R. Meneely, R. G. Tucker, and W. J. Darby, “Chronic Sodium Chloride Toxicity in Albino Rat. 1. Growth on a Purified Diet Containing Various Levels of Sodium Chloride,” J. Nutr., 48, 489 (1952). G. R. Meneely, R. G. Tucker, W. J. Darby, and S. H. Auerbach, “Chronic, Sodium Chloride Toxicity in Albino Rat. II. Occurrence of Hypertension and Syndrome of Edema and Renal Failure,” J. Exptl. Med., 98, 71 (1953). G. R. Meneely, R. G. Tucker, W. J. Darby, and S. H. Auerbach, “Chronic Sodium Chloride Toxicity; Hypertension, Renal and Vascular Lesions,’ Ann. Internal Med., 39, 991 (1953). G. R. Meneely, C. O. T. Ball, and J. B. Youmans, “‘Chronic Sodium Chloride Toxicity: Protective Effect of Added Potassium Chloride,” Ann. Internal Med., 47, 263 (1957).

SODIUM CHLORIDE 279 G. R. Meneely and C. O. T. Ball, “‘Experimental Epidemiology of Chronic Sodium Chloride Toxicity and Protective Effect of Potassium Chloride,” Am. J. Med., 25, 713 (1958). G. R. Meneely, “Salt,” Am. J. Med., 16, 1 (1954). G. R. Meneely and L. K. Dahl, “Electrolytes in Hypertension: The Effects of Sodium Chloride. The Evidence from Animal and Human Studies,” Med. Clin. N. Am., 45, 271 (1961). G. W. Pickering, High Blood Pressure, Grune & Stratton, New York (1955). R. Platt, ““The Nature of Essential Hypertension,” Lancet, ii, 55 (1959). W. D. Reid and J. H. Laragh, “Sodium and Potassium Intake, Blood Pressure, and Pressor Response to Angiotensin,” Proc. Soc. Exptl. Biol. Med., 120, 26 (1965). L. A. Sapirstein, W. L. Brandt, and D. R. Drury, “Production of Hypertension in Rat by Substituting Hypertonic Sodium Chloride Solutions for Drinking Water,” Proc. Soc. Exptl. Biol. Med., 73, 82 (1950). N. Sasaki, ‘“‘High Blood Pressure and the Salt Intake of the Japanese,” Japan. Heart J., 3, 313 (1962). N. Sasaki, “The Relationship of Salt Intake to Hypertension in the Japanese,” Geriatrics, 19, 735 (1964). H. Selye, C. E. Hall, and E. M. Rowley, “Malignant Hypertension Produced by Treatment with Desoxycorticosterone Acetate and Sodium Chloride,” Can. Med. Assoc. J., 49, 88 (1943). H. A. Schroeder, Hypertensive Diseases: Causes and Control, Lea & Febiger, Philadelphia, Pa. (1953). J. R. Smith, “Salt,” Nutr. Rev., 11, 33 (1953). W. R. Smith, “Salt: Ancient History and Religious Symbolism,” Encyclopaedia Britannica, 11th ed., Cambridge University Press (1911), Vol. 24, p. 87. E. Takahashi, ‘“‘An Epidemiological Approach to the Relation Between Diet and Cerebrovascular Lesions and Arteriosclerotic Heart Disease,” Tohoku J. Exptl. Med., 77, 239 (1962). C. B. Thomas, “Familial Patterns in Hypertension and Coronary Heart Disease,” Circulation, 20, 25 (1959). R. G. Tucker, C. O. T. Ball, W. J. Darby, W. R. Early, R. C. Kory, J. B. Youmans, and G. R. Meneely, ‘Chronic Sodium Chloride Toxicity in Albino Rat. III. Maturity Characteristics, Survivorship and Organ Weights,” J. Gerontol., 12, 182 (1957). Sodium and Potassium Analyses of Foods and Waters, Fifth List, Mead Johnson & Co., Evansville, Ind. (Oct. 1947).

J. M. COON Discussion It is evident from the foregoing reviews that a multitude of chemical substances having recognized toxic properties are present in many of the natural foodstuffs that may enter into the diet of man. It has not been feasible to attempt a comprehensive coverage of what is known in this field, and the selection of specific topics for detailed review has been somewhat arbitrary. Numerous important and well-known, or interest- ing and not so well-known, examples of toxic substances naturally present in foods have not been mentioned. Some of these might profit- ably be cited here to illustrate further the extent of the possibilities, as well as to emphasize that the nature and scope of our present knowledge demonstrate its own incompleteness. Many chemical entities with toxic properties undoubtedly remain to be discovered in natural food products, and the significance of many known ones to the health of man through his consumption of the foods containing them has yet to be determined. The solanine alkaloids of the potato have caused many cases of poisoning in man, especially under circumstances of unusual consump- tion involving the sprouts, eyes, and skin. Exposure of freshly harvested potatoes to sunlight increases the solanine content, and a level of more than 0.1 percent of the alkaloid has been considered to render the potato unfit for human consumption.! A factor in buckwheat is responsible for fagopyrism, a form of photosensitization. This has not been a problem in man, but cattle develop the syndrome, which is characterized by an inflammation of the eyes, nose, and ears when buckwheat is included in their forage. Photosensitization has been reported from the handling of parsnips.2 Naringen, a glycoside present in unripe grape- 280

DISCUSSION 281 fruit, is irritating to the gastrointestinal tract. Lycopene, an aliphatic hydrocarbon related to carotene, accumulates in the liver and has caused illness in man as a result of the chronic consumption of large quantities of tomato juice. Phytates in cereals tend to reduce the assimilation of calcium from the diet. Prunes contain derivatives of hydroxyphenylisatin that have potent laxative activity by virtue of their gastrointestinal irritant properties.4 Certain purines and pyrimidines have been reported to promote the atherogenic activity of an athero- genic diet in experimental animals.5 Outbreaks of honey poisoning have been reported in the United States and Europe. The honey became poisonous when bees collected the nectar from certain plants, e.g., mountain laurel, rhododendron, oleander, and azalea, that contain highly toxic cardioactive glycosides. Disulfiram, a chemical substance known to interfere with the normal metabolism of alcohol, has been reported to be present in an edible mushroom, “inky cap” (Coprinus atramentarius). Several cases of acute illness have resulted from the drinking of an alcoholic beverage following the consumption of this mushroom.’ It has been reported that both the white and the yolk of the hen’s egg are carcinogenic when fed to mice.8 Carbohydrates are universally present and needed in the diet of man. Highly refined carbohydrates in the diet seem to be causally associated with one of his most common diseases, dental caries. Several natural polysaccharides (gums, pectin, and dired okra) have been reported to inhibit the growth of chickens at a 2 to 4 percent level in the diet.9 Lactose and fructose can be said to be toxic in infants with a hereditary absence of the enzymes that normally metabolize these sugars, giving rise to the syndromes of galactosemia and fructosemia, respectively. The cataractogenic property of lactose and galactose in rats is well known. An intolerance to wheat gluten has been described in children and is thought also to be due to an inborn error in the metabolism of an unidentified component.!0 Of the trace elements that occur naturally in foods, copper, cobalt, iron, manganese, and zinc are discussed in some detail in ‘Toxicity of the Essential Minerals,”’ page 229 and selenium is discussed in ““Tumori- genic and Carcinogenic Natural Products,” page 24. Numerous other elements with long-standing reputations for their general toxicologic significance may be mentioned. Arsenic and fluorine are widely distributed in plant and animal food sources, the highest levels occurring in seafoods, which also contain iodine. Eggs contain lead, as well as arsenic, fluorine, iodine, bromine, and phosphorous. Chromium is present in dairy products, meat, fish, and fat. Molybdenum occurs in

282 J. M. COON numerous broad-leaved plants, espectally in cabbage, cauliflower, and potato, and produces chronic toxic effects in cattle and sheep foraging on vegetation growing in soils containing high levels of this element. Cadmium, an element of relatively high toxicity, is present in many foods, usually in association with zinc, for which it is considered an antimetabolite. Cadmium accumulates in the kidney and liver through life, and since an elevated ratio of cadmium to zinc commonly occurs in hypertension, this has been suggested as a factor in the pathogenesis of the disease.!! Hypertension has been induced experimentally in rats by small amounts of cadmium in the diet.!2 A miscellany of this sort could be greatly extended and many readers and workers in the field will be able to add other examples of naturally occurring substances that (a) are known to have caused injury to man through his food, (b) have produced adverse effects when fed in sufficient amounts to experimental animals, or (c) are suspected on the basis of other considerations to have harmful potentialities. Throughout history man has accumulated the experience and knowledge, largely from empirical observations through trial, error, illness, and death, that have lead to the classification of natural plant and animal products into two categories, those safe and those unsafe for consumption as food. Many if not most of the decisions that placed products in the unsafe category were undoubtedly based on the observa- tion of harmful effects that occurred so soon after eating that they were the obvious result of the consumption. The reviews in the present monograph make it clear, however, that many natural products that have found wide acceptance for use as foods are considered safe, not because they contain no toxic substances, but because they do not contain enough to produce harmful effects, insofar as we know, under the ordinary circumstances of preparation and patterns of consumption. There is little concern in regard to the acute toxicity of many of the known toxic substances in foods, for example, oxalates, cyanogenetic glycosides, cholinesterase inhibitors, solanine alkaloids, goitrogens, estrogens, arsenic, lead, selenium, and fluorine. The challenge that we do face, however, is the question of the long- term chronic toxicity, or lifetime effects, of many of the known as well as the as yet unrecognized natural chemical components of our foods. Long-delayed harmful effects that might result from normal patterns of consumption are of the greatest potential importance since they would be expected to affect a large number of individuals. The accumulation of new knowledge of this nature will be subject to the difficulties inherent in relating such slowly developing effects to their specific

DISCUSSION 283 causes in the complex chemical context of the total diet. The relation- ships of goiter, lathyrism, favism, and ergotism with their specific dietary causes were slow in coming to light. It will be even more difficult to determine whether such tumorigens of experimental animals as safrol, selenium, tannins, and cholesterol, by virtue of their presence in many common food items, are responsible for any form of malignant disease in man, or whether sodium chloride or cadmium may play a role in the pathogenesis of hypertension. These possibilities require further study and such substances will be held suspect by some until knowledge is developed to remove or confirm the suspicions. The role of the dietary in the development of the degenerative diseases in general should be considered, not only from the viewpoint of the quantity and balance of the essential nutrients, but also in the light of the nonnutrient chemical substances present in the natural sources of the diet. Progress in this regard will require a much more complete knowledge than we have now of the nonnutrient chemical substances that are present in natural food sources, and of their chronic toxicologic actions and interactions. It has been noted that, though the natural sources of man’s foods contain many chemical substances that are known to have nondietary toxicologic significance, most of them are not known to be harmful to normal healthy human beings consuming what has been established as a reasonable balanced diet, prepared in time-honored ways. Adequate cooking reduces or destroys the harmful properties of the cyanogenetic glycosides in the lima bean, the goitrogens in certain vegetables, thiaminase in fish, and avidin in the egg. After ripening, the ackee fruit and grapefruit lose their toxic components. Natives of the tropics extract the toxic cycads with water to obtain an edible starch. But the most important protection against injury from the natural chemicals in foods appears to derive from the fact that most of them are present in such small quantities that grossly abnormal patterns of consumption are necessary to reveal the toxic potential of any single substance. This, of course, is in accord with the generally accepted view that for almost any toxic substances there is an intake level below which no detectable deleterious effect occurs. In certain types of poisoning by the natural components of foods, however, the intake of large quantities of the food is not responsible. In the case of the toxins in seafood, cardioactive glycosides in honey, tyramine in cheese, and disulfiram in the “inky cap” mushroom, unexpected hazards arise from unpredictable combinations of cir- cumstances. Also, it is apparent that the ranges of safety for the natural

284 J. M. COON components of foods are not wide enough, in certain instances, to allow for even normal patterns of consumption, as in the presence of the increased sensitivities associated with diseased states, inborn errors of metabolism, allergic sensitivities, or individual nonspecific intolerances. A normal daily intake of sodium, for example, is considered deleter ous to the hypertensive patient, and liver and kidney diseases are notable for increasing the sensitivity to toxic chemicals that are normally metabolized or excreted by these organs. It seems reasonable that the same attention, toxicologically, should be given to chemical substances that occur naturally in foods as has been given to the additives and pesticide residues that are associated with our food supply as a result of man’s efforts to improve it. At present, the unknowns in regard to the chemical makeup and toxicology of our natural food sources seem much more extensive and numerous than those related to additives and residues. No diversion of attention from the latter to the former, however, is suggested. In fact, considera- tion should be given to the additional potential problems that might arise from the simultaneous presence and the consequent chemical and toxicologic interactions of these two groups of materials. As far as nian’s food intake is concerned, our ultimate goal is to achieve a knowledge not only of what, under various circumstances, constitutes the optimum in the nutritional content, but also of what involves. the minimum of long-range toxicologic hazard in the diet. REFERENCES 1. W. F. Talburt and O. Smith, Potato Processing, The Avi Publishing Co., Westport, Conn. (1959), p. 30. 2. T. Sollmann, A Manual of Pharmacology, 8th ed., Saunders, Philadelphia, Pa. (1957), p. 163. 3. P. Reich, H. Schwachmar, and J. M. Crain, “‘Lycopenemia: A Variant of Carotenemia,”” New Engl. J. Med., 262, 263 (1960). 4. G. A. Emerson, “The Laxative Principle in Prunes,” Proc. Soc. Exptl. Biol. Med., 31, 278 (1933). 5. L.C. Fillios, C. Naito, S. B. Andrus, and A. M. Roach, “The Hypercholestere- mic and Atherogenic Properties of Various Purines and Pyrimidines,” Am. J. Clin. Nutr. 7,70 (1959). 6. F. M. Carey, J. J. Lewis, J. L. MacGregor, and M. Martin-Smith, “‘Pharmaco- logical and Chemical Observations on Some Toxic Nectars,” J. Pharm. Phar- macol., II, 269T (1959). 7. W. A. Reynolds and F. H. Lowe, “Mushrooms and a Toxic Reaction to Alcohol,” New Engl. J. Med., 272, 630 (1965).