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The need for common salt in the diet is an ancient, inveterate cognition, deeply rooted in human mores, to such an extent that little thought has been given to the chronic toxicity of sodium chloride. A search of the literature reveals a number of papers which describe toxic effects of sodium chloride in fowl (1), but a paucity of information relative to mammals. Campbell (2) reported the possibility of kidney damage in the rat fed a diet containing more than 5 per cent of sodium chloride. Mosier (3) studied the adrenal glands in rats on diets very high in sodium chloride. Sapirstein, Brandt, and Drury (4) and Gross (5) produced hypertension in rats fed diets high in sodium chloride and restricted in the amount of fluid. This was accomplished by substituting saline solution for drinking water. Binet, Dejours, and Lacaisse (6) raised rats on a high sodium chloride regimen and described a resulting renal hypertrophy and functional adaptation. A few experiments of a chronic nature have been made using the mouse (7), the albino and the kangaroo rat (8), the dog (9), and the cow (10).Recently Meneely, Tucker, and Darby (11) reported on the growth of rats fed for 20 weeks on purified diets containing seven different levels of sodium chloride. The present paper describes certain pathologic manifestations of chronic sodium chloride toxicity which were observed in these animals. Abstracts of these findings have appeared (12). Materials and MethodsThe experimental regimen has been described (11). Male, albino, Sprague-Dawley rats, weighing an average of 119 gm., were placed on purified rations and demineralized water ad libitum. The purified rations contained seven different levds of sodium chloride as follow: ration I (low Na diet), about 0.01 per cent Nat1; ration II (control diet), 0.15 per cent NaCI; ration III, 2.8 per cent NaCI; ration IV, 5.6 per cent NaC1; ration V, 7.0 per cent NaCI; ra-71

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A method for measuring the volume of fluid available for the distribution of sodium (sodium space) by the use of its radioactive isotope (Na24) has been described and the accuracy of the method has been discussed. Simultaneous determinations of the plasma volume by means of the blue dye T-1824 and the volume of the extracellular fluid by employing radiosodium and sodium thiocyanate have been made in normal subjects. Repeated measurements were made at varying periods of time in the same individuals. In order to establish the rate of diffusion equilibrium for the radioactive isotope of sodium and thiocyanate between serum and serous effusions, simultaneous samples of both were obtained at varying intervals after the intravenous injection of these substances. Since evidence in the literature indicates that there is an excess of sodium mainly limited to bone, which cannot be attributed to the extracellular phase, experiments on dogs and man were so devised that the ratio of tissue concentration to plasma concentration for radiosodium and chemically determined chloride could be calculated. The following conclusions may be drawn from the results of this investigation: 1. Radiosodium after intravenous administration spreads rapidly during the first 3 hours from the plasma into a volume of fluid which represents approximately 25 per cent of the body weight of man. Thereafter for 6 hours it diffuses more slowly into certain tissue spaces—the central nervous system and probably the skeleton. The plasma volume and interstitial fluid represent 15 and 85 per cent of the sodium space respectively. 2. Diffusion equilibrium for both radiosodium and thiocyanate is not established between serum and transudates in edematous patients until from 9 to 12 hours after the intravenous injection of these substances. 3. Until more complete information is available, it is concluded that unless the difference between repeated observations on the same individual exceeds ±1.38 liters there is no significant change in the sodium space providing that the activity of the standard and serum samples are in the range of 40 counts per minute per milliliter with the counting apparatus used. As the activity of the samples increases, the error becomes less because there is no correlation between the magnitude of the error and the magnitude of the activity. 4. Climatic conditions produce no significant changes in the volume of the blood or extracellular fluid. 5. In the dog, following the intravenous injection of radiosodium, the concentration of the isotope in bone reaches its maximum rapidly (3 hours). The extra sodium in the skeleton of dog is equal to about ¼ of the total counts in the body, assuming that the chloride space of bone represents its extracellular volume. Similar amounts of excess sodium are found in the skeleton of man 12 hours after the administration of Na24. 6. Correction of the sodium space of man for the excess sodium reduced the average value by 3.7 liters or 18.9 per cent. The average corrected volume for the normal subjects 6 hours after the injection is 15.9 liters or 21.1 per cent of the body weight compared with the thiocyanate space of 17.7 liters, representing 23.5 per cent of the body weight. 7. The most useful method for calculating the sodium space from the data obtained after intravenous administration of radiosodium is as follows: See PDF for Equation This space exceeds the volume of extracellular fluid by the amount of excess sodium in the body that cannot be attributed to the extracellular phase. 8. While neither the thiocyanate method nor the radiosodium method gives precise estimates of the extracellular fluid, the error is of the same order of magnitude in both. For clinical use, the thiocyanate method is superior because of the ready availability of the substance, and the apparatus required.

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