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STUDIES OF CALCIUM AND PHOSPHORUSMETABOLISM

XIII. TirE EFFECTOF INGESTION OF PHOSPHATESONTHE EXCRETIONOF CALCIUM'

BY RAY F. FARQUHARSON,2WILLIAM T. SALTER, AND JOSEPHC. AUB(From the Medical Clinic of the Massachusetts General Hospital, Boston)

(Received for publication November 26, 1930)

Most of the calcium of the body is found combined with phosphatein the skeleton but phosphorus in one form or another is present inrelatively large quantities in all body tissue. Any gross change incalcium metabolism must of necessity affect the phosphorus output.It might be possible, however, for considerable changes to occur inphosphorus metabolism without any great effect on the calciumbalance,

In the metabolism of bone the two elements are closely associatedand under certain abnormal conditions their mutual interdependenceis strikingly demonstrated. It has been clearly shown, for instance,(1, 2, 3, 4, 5, 6) that in growing animals the ratio of these two elementsin the diet is of the greatest importance and that in the absence of thecontrolling influence of vitamin D any great departure from theoptimal relationship of calcium and phosphorus in the food results inthe development of rickets. In the rachitic child or rat, also, Karelitzand Shohl (7) and Shohl and Brown (8) found that the ingestion ofadded phosphate brought on tetany with the characteristic fall inserum calcium and rise in serum phosphorus.

It is well known that in many conditions there is a definite relation-ship between the values for calcium and phosphorus in the serum.3 In

1 Aided in part by a grant from the Lead Fund of Harvard University.2 Alexander McPhedran Research Fellowship in Clinical Medicine, University

of Toronto.The term "serum phosphorus" is used with reference to serum inorganic

phosphorus throughout this paper.251

THU JOURNALOF CLNICAL INVUSTIGATION, VOL. X, NO. 2

EFFECT OF INGESTION OF PHOSPHATES

tetany, whether infantile, idiopathic, or after parathyroidectomy, thelow serum calcium is almost always associated with a high serumphosphorus. A similar relationship was found to exist in terminalnephritis by Marriott and Howland (9), DeWesselow (10), and others.In hyperparathyroidism, on the other hand, whether induced by in-jections of parathyroid extract or present as a pathological state(11, 12, 13, 14, 15), the serum calcium is high and the serum phosphoruslow. In those conditions characterized by low serum calcium and highserum phosphorus the excretion of calcium in the urine tends to bediminished. When, on the other hand, the serum calcium is high andserum phosphorus low, the excretion of both in the urine is increased.

In exophthalmic goiter, Aub, Bauer, Heath, and Ropes (16) foundassociated with a greatly increased urinary excretion of calcium andnitrogen a corresponding increase in the phosphorus excretion. Theconverse was found to be true of myxedema. Tn neither case wereserum levels changed appreciably.

It was first observed by Binger (17) that in dogs the injection oflarge amounts of neutral phosphate caused a marked lowering of theserum calcium with the development of tetany. Tisdall (18) obtainedsimilar results and Salvesen, Hastings, and McIntosh (19) found thatingestion of very large quantities of inorganic phosphate, whether acidor basic, had the same effect. Injection of phosphate in dogs wasfound by Greenwald and Gross (20) to cause an increased excretion ofcalcium which persisted for several days. Ingestion of excess phos-phorus in children has also been found to result in an increased loss ofcalcium in the feces (21).

Although such close relationship has been found in the metabolismof calcium and phosphorus, no careful studies have been made of theinfluence of changes in the phosphorus intake on the calcium metab-olism of human adults. The effects noted above, of injection oringestion of phosphate, were produced in dogs by tremendous quantitieswhich were far in excess of any physiological variation in the phos-phorus intake. The purpose of the present investigation was to studythe effect of great variations in the ingestion of phosphorus on thecalcium balance of adults who had no disorder likely to affect theinorganic salt metabolism. Experiments were planned to differentiateclearly the influence of the phosphate radicle itself from that of the

252

R. F. FARQUHARSON,W. T. SALTER AND J. C. AUB

acid or basic properties of its various salts as weH as from any possibleeffect of an increased nitrogen metabolism when the phosphorusintake was increased by feeding a high protein diet.

EXPERIMENTALPIROCEDURE

Most of the patients were given a control diet low in calcium andphosphorus but adequate with respect to other inorganic salts, vitamins,fat, carbohydrate, protein, and total caloric content, as described in aformer paper (22). This control diet was so constituted as to give aneutral inorganic residuum when oxidized. When there was ofnecessity an excess intake of acid radicles, as in a high protein diet, theacid effect was controlled by the administration of an appropriateamount of sodium bicarbonate with' each meal. Urine and stoolswere collected and prepared in three-day periods, as formerly described(22), the specimens for the first three days being discarded. When-ever possible a further nine days was allowed for an initial observationperiod, nine days for testing each change in regimen, and an after-period of nine days for return to equilibrium before another changewas instituted.

METHODS

Calcium determinations were made by Fiske's method (23). Thismethod has been found to be thoroughly dependable and more ac-curate than methods previously used, especially under conditions whenlarge amounts of phosphate are excreted. Inorganic pbosphorus,urinary ammonia, titratable acidity of the urine, and total base, weredone by the methods of Fiske and Subbarow; Folin; Henderson andPalmer; and Fiske, respectively, under conditions or minor alterationsas previously described (22).

EXPERIMENTSAND RESULTS

The effect of large doses of acid sodium phosphateWN, a married woman of thirty-four years of age, suffering from

chronic atrophic arthritis, was given throughout the whole period ofobservation the same basal diet low in calcium and phosphorus, andpotentially neutral. After a nine-day control period 15 grams ofNaH2PO4. 2H20 was given daily for eight days. Observations were

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continued for another nine-day after-period. Early in the after-periodthe patient had an acute upper respiratory infection with a fever of1020. This condition, however, subsided quiddy without having anyobvious effect on the excretion of eith'er calcium or phosphorus. Ithad previously been shown that chronic fevers (16) failed to altermaterially the calcium and phosphorus metabolism. The results aregiven in table 1.

It is quite clear that the ingestion of acid sodium phosphate, in suchquantity that the phosphorus intake was increased to more than fivetimes that of the control diet, had no appreciable effect on the excre-tion of calcium in either urine or feces. The average negative calciumbalances for the initial control periods, the periods of administrationof acid phosphate, and the final control periods were -0.50, -0.53, and-0.60 grams respectively. It is to be noted also that the increase inthe titratable acidity of the urine in response to the ingestion of acidphosphate was much greater than that of the urinary ammonia. Eventhe slight increas'e in the ammonia excretion that occurred in thispatient on the ingestion of acid phosphate is unusual. It is difficultto explain the further rise in ammonia excretion during the after-period,unless it be in some way associated with the acute infection from whichthe patient suffered in period VII. It is obviously not related to anincreased phosphorus excretion.

Comparison of effects of ingestion of equal amounts of phosphorus as acidand as basic phosphate

In order to distinguish between the effect of the phosphate radicleand that of the acid or basic qualities of its salts, a patient, while main-tained on a constant control diet low in calcium and potentially neutral,was given at appropriate intervals about 2.3 grams of phosphorusdaily, first as Na2HPO4 and then as NaH2PO4. RN, a woman ofthirty-nine years of age, weighing fifty-six kilos, hid suffered fromrheumatic heart disease (mitral stenosis), chronic bronchitis, andbronchial asthma. During the period of observation, and for sometime before, however, she had no cough, her chest was clear, and therewere no signs of myocardial failure. She was comfortable and lookedwell. In period X, while receiving acid phosphate, she had some

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diarrhea but it ceased after a day or two. Results are presented intable 2.

Again, it can be seen that the ingestion of large doses of phosphate,acid or basic, had no appreciable effect on the excretion of calcium ineither urine or stool. When the disodium salt was fed the urine becamealkaline and the ammonia excretion fell off but the excretion of calciumremained within the limits found in the initial control periods. Onadministration of acid phosphate the titratable acidity of the urine rosegreatly while the ammonia and calcium excretion remained at basallevels. In both cases, even when there was diarrhea, the great bulk ofthe phosphate was absorbed and the urinary phosphorus was alwaysmuch greater than the fecal phosphorus. There was also a markedretention of phosphorus.

The acid effects of NaH2PO4Jn studying the influence of ingestion of various types of acid-yielding

substances on the calcium and phosphorus metabolism, approximatelyequal amounts of "potential acid" were fed at appropriate intervals,first in the form of foodstuffs, then as NH4Cl, and later as NaH2PO4,to a patient, DA, who was recovering from chronic lead poisoning.He was thirty-seven years of age, weighed thirty-eight kilos, wascomfortable, and took his food well and willingly throughout the wholeperiod of observation. The calcium intake was constant and, exceptduring the period when an acid diet was given, the same constantneutral low calcium diet was taken throughout. Results are presentedin table 3.

The sum of the ammonia excretion and titratable acidity of theurine is considered here, as in our other work, to give the best indica-tion of the potential acid value of the ingested food or medication. Inthis experiment approximately equal values for this "total acid" ofthe urine were obtained during the ingestion of an acid diet, on ad-ministration of 4 grams of NH4Cl daily, and on administration of2.66 grams of phosphorus in the form of NaH2PO4daily. After theperiods in which he received 4 grams NIHCl daily the dose was in-creased to 12 grams per day for two more periods. In response to thislarge amount of acid ingested there was a very great production of

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ammonia,4 and this high level of ammonia excretion persisted on intothe after-control period and unfortunately had not yet reached asteady state when the acid phosphate was given, nine days later. Thenature of the response to NaH2PO4is, nevertheless, clear.

The different types of acid administered provoked a distinctly differ-ent response as reflected in the nature of the increased acid in the urine.It has been pointed out elsewhere (24) that although the total acidoutput of the urine was approximately equal for the three types of acidingested, nevertheless, when the acid was given as excess acid in thefood or as NH4CI, the brunt of the burden was borne by increasedammonia production, and the titratable acidity of the urine was onlyslightly increased. When acid phosphate was given, however, thetitratable acidity increased greatly and the ammonia excretion, stillhigh after the ingestion of NH4CI, continued to fall while acid-phos-phate was taken. In the second phosphate period it was only slightlyhigher than that of the control periods.

There was likewise a very great difference in the effect of thedifferent types of acids on the calcium excretion. Those whoseingestion was associated with great ammonia production also gave riseto a considerable increase in the calcium excretion in the urine. Theingestion of NaH2PO4, on the other hand, which produced only anincreased titratable acidity, was associated not with increased calciumexcretion but actually with a slightly diminished output of calcium inthe urine. The values for calcium in the feces were little affected bythe different types of acid fed, although like those for the urine thelowest values for calcium in the feces of the whole period of observa-tion were obtained during the administration of NaH2PO4.

The results of these three experiments show that the ingestion oflarge amounts of inorganic phosphate, whether acid or basic, falls to

influence appreciably the excretion of calcium in either urine or feces inadults on a low calcium diet. The intake of phosphorus in theseinstances was much greater than could be fed in any diet of naturalfoodstuffs, corresponding as it did to the phosphorus content of a dietcontaining well over 200 grams of protein.

4That the increased excretion of ammonia which follows on ingestion of NH4Clis not due to an increased intake of "ammonia" has been clearly shown in anotherpaper (24). The great excretion of ammonia fell to control levels when an ap-propriate amount of NaHCO3was ingested between doses of NH4Cl.

260


Effect of food rich in phosphorus

In hyperthyroidism (16) it had been found that a greatly increasedexcretion of calcium and nitrogen was associated with a correspondingincrease in the phosphorus output. To ascertain whether a diet highin protein (i.e. high in phosphorus) wouId affect the calcium metab-olism, 200 grams of protein per day were fed to a healthy normalindividual, aged thirty, weighing seventy-eight kilos. In the previousnine days the subject had taken a neutral control diet of approximatelythe same low calcium content as that of the high protein diet. Duringthe first nine days of the high protein diet sufficient NaHCO3wastaken with the meals to prevent an increase in the "total acid" excre-tion of the urine, thus eliminating the acid effect of the high proteindiet. Results are given in table 4.

On the ingestion of large quantities of protein there was a gradualbut definite increase in the calcium excreted in the urine associatedwith an almost equal decrease in the calcium of the feces, so that thecalcium balance for the period of high protein diet plus NaHCO3wasvirtually the same as for the control period. The high protein diet hada low residue and during its administration the stools were smaller thanformerly although there was no tendency toward constipation. Thelower calcium of the stool may be accounted for, in part at least, bythe smaller bulk of the feces, as suggested by observations of Sjollema(25). The phosphate of the feces was little increased and afterNaHCO3was discontinued it was actually slightly less than that of thecontrol periods. Phosphorus in the urine increased to over 4 grams,and even on such high intake there was a slight negative phosphorusbalance.

The very high protein diet had no appreciable effect on the calciumbalance so long as NaHCO3was taken to neutralize its acid effect.When the NaHCO3was discontinued the ammonia, titratable acidity,and calcium of the urine all rose but the experiment had to be dis-continued before the full effect could be observed.

Moderate calcium diet-Effect of ingestion of added phosphate

All of the previous experiments had been done on patients taking alow calcium diet. The effect of equal amounts of phosphate, first in a

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high protein diet and then as added (nearly) neutral inorganic phos-phate, was now studied on a patient receiving a moderate calciumintake of about 0.5 gram per day instead of 0.1 gram previously given.LZ, aged eighteen years, weighing sixty kilos, was slowly recoveringfrom chronic multiple neuritis. He was confined to bed throughoutthe whole period of observation but looked and felt fairly well. Aftertwo periods on a diet containing 0.50 gram calcium and 66 grams proteinper day he was given a diet of the same calcium content but containingabout 120 grams of protein per day. NaHCOwas added to control theacidity. Later, after an interval of nine days on the control diet, hewas given approximately the same amount of phosphorus in an equi-molecular mixture of NaH2PO4and Na2HPO4. Results are presentedin table 5.

The calcium excretion in the urine of this patient was higher than isusual. On an intake of 0.50 gram per day there was in the controlperiods an average negative calcium balance of 0.44 gram per three-dayperiod. He was kept on the high protein diet for eighteen days, duringall of which time he was given NaHCO3. The average value forurinary calcium of the high-protein penrods is almost exactly the sameas that for the preceding and for the following control periods. Duringthe high protein diet, however, the stools were very much larger thanin the control periods, and their calcium content was definitely, al-though not greatly, increased. There was, accordingly, a greaternegative calcium balance during the period of high protein diet. Thisfinding is quite the reverse of that obtained in subject R. F. F. on ahigh-protein diet. In R. F. F., however, during the ingestion of thehigh protein diet the stools were smaller than in the control periods.It seems reasonable to attribute the larger output of calcium in thestools of LZ not to any specific effect of increased ingestion of proteinand phosphorus but rather to associate it with the greater fecal bulk(due to other causes).

The subsequent administration of 1.1 gram of phosphorus as anequimolecular mixture of Na2HPO4and NaH2PO4resulted in a slightdecrease in ammonia and a definite decrease in the calcium of theurine. The size and calcium content of the stools was rathervariablebut it is clear the administration of inorganic phosphate failed to causean increase in fecal calcium excretion. The excretion of phosphorus

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in both urine and feces was higher on the high protein diet than whenthe same amount of phosphorus was fed as inorganic phosphate.

In this patient receiving a moderate calcium intake the ingestion oflarge amounts of phosphorus either in protein or as inorganic phos-phorus had produced no great effect on the calcium balance. In hiscase, however, as in the case of DA, the taking of large amounts ofinorganic phosphate was associated with a definite but not great fallin the calcium output in the urine.

Effect of ingestion of phosphate on the serum calciumIn the various experiments blood was taken during fasting just

before making a change in phosphorus intake. Under such conditionsthere was at no time an appreciable change in the serum calciumexcept that in the case of DA the serum calcium was slightly loweredafter ingestion of large doses of NaH2PO4.

In one subject blood determinations were made at frequent intervalsafter a single dose of 3 grams of phosphorus as nearly neutral phos-phate. Although the serum phosphate rose from 3.4 mgm. to 5.0mgm. the serum calcium values were not affected. These results arediscussed more fully in another paper (26).

COMMENT

These metabolic studies, with one exception, were made on adultsgiven a diet which was neutral and adequate except in calcium. Widevariation in the ratio of phosphorus to calcium in the intake appearsto have but little effect on the excretion of calcium in either urine orfeces, or on the calcium balance. Even when the phosphorus intakewas increased fivefold the only effect noted was a slight lowering ofthe calcium of the urine in one case. In the patient studied on a highercalcium intake, the effect of more than doubling the phosphorus intakewas similarly negative.

When the acidity of a high protein diet was controlled by the addi-tion of NaHCO3there was likewise no appreciable effect of such highphosphorus and protein intake on the calcium balance in patients onlow or moderate calcium intakes.

The amounts of inorganic phosphorus fed were in general the largestthat could be taken without the development of diarrhea. In all

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cases the stools tended to be a little loose and in one case there was milddiarrhea for a day or so. The absorption of phosphate-, however, wasgood and although phosphorus in the feces was always increased yetit was never nearly so great as that of the urine. Usually aboutthree-fourths of the extra phosphorus output was excreted in urine.When inorganic phosphate was fed there was in all cases definitephosphorus retention. In the two cases on high protein diet there wasa slight negative phosphorus balance.

In another paper (27) attention is drawn to the fact that in periodsof great phosphate ingestion there was not sufficient total fixed basein the feces to bind the phosphate present as tribasic phosphate, to saynothing of the amount of calcium that would be required to do so. Ithas been erroneously assumed by some investigators that the Ca/Pratio in the stools can per se be used as evidence for or against thestatement that calcium is excreted as a tribasic salt. Under the con-ditions of our experiments it is quite clear that the ingestion of largeamounts of phosphate has had no tendency to increase the eliminationof calcium in the feces materially. As to the precise form in whichthe calcium existed, we have no evidence.

The failure of ingested NaH2PO4to act like other acids in inducingan increased excretion of ammonia in the urine is discussed elsewhere(24). In our experiments, whenever ingestion of acid was associatedwith definitely increased ammonia production the calcium excretionwas also increased. The ingestion of NaH2PO4 in all cases resultedin little or no increase in ammonia and no increase in calcium elimina-tion. Increase in ammonia and calcium of the urine are probablyseparate but parallel responses to the same stimulus. Variation in theammonia output, however, appears to be the best indication as to theeffect of a given "acid" on the calcium excretion. With regard tocalcium metabolism, therefore, the acid value of a diet is better mea-

sured by its effect on ammonia production than by the "total acid"output (i.e., ammonia plus titratable acidity).

SUMMARY

The effect of large variation of the phosphorus intake, inorganic andorganic, on the calcium metabolism of adults receiving a low or

moderate calcium intake has been described.

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Great variation in the phosphorus intake and, therefore, in theP/Ca ratio failed to affect materially the excretion of calcium ineither urine or feces, although in two cases administration of inorganicphosphate resulted in a slight but definite decrease of the calcium of theurine.

Ingestion of a very high protein diet had no appreciable effect on thecalcium balance when the acid effect of the protein was controlled byadministration of NaHCO3.

Ingestion of NaH2PO4 gave rise to a great increase in titratableacidity of the urine but had little effect on the excretion of ammonia orcalcium. In this it differed from other acid-producing substancesstudied, which resulted in increasing both the ammonia and calciumof the urine.

BIBLIOGRAPHY

1. Sherman, H. C., and Pappenheimer, A. M., Proc. Soc. Exp. Biol. and Med.,1921, xviii, 193. A Dietetic Production of Rickets in Rats and Its Preven-tion by an Inorganic Salt.

2. Shipley, P. G., Park, E. A., McCollum, E. V., and Simmonds, N., Bull. JohnsHopkins Hospital, 1921, xxxii, 160. Studies on Experimental Rickets.III. A Pathological Condition Bearing Fundamental Resemblances toRickets of the HumanBeing Resulting from Diets Low in Phosphorus andFat Soluble A. The Phosphate Ion in its Prevention.

3. McCollum, E. V., Simmonds, N., Shipley, P. G., and Park, E. A., J. Biol.Chem., 1921, xlvii, 507. Studies on Experimental Rickets. VIII. TheProduction of Rickets by Diets Low in Phosphorus and Fat Soluble A.

4. McCollum, E. V., and Simmonds, Nina, Newer Knowledge of Nutrition.New York, 1929, 4th ed., Chapter XIX.

5. Shohl, A. T., Bennett, H. B., and Weed, K. L., J. Biol. Chem., 1928, lxxix, 257.Rickets in Rats. VII. Metabolism of Calcium and Phosphorus of RatsFed upon Non-Ricketogenic Diets.

6. Brown, H. B., and Shohl, A. T., J. Biol. Chem., 1930, lxxxvi, 245. Rickets inRats. XI. The Alteration of Calcium and Phosphorus Metabolism ofNormal and Ricketic Rats Produced by Irradiated Ergosterol.

7. Karelitz, S., and Shohl, A. T., J. Biol. Chem., 1927, lxxiii, 665. Rickets inRats. II. The Effect of Phosphorus Added to the Diet of Ricketic Rats.

8. Shohl, A. T., and Brown, H. B., J. Biol. Chem., 1929, lxxxiv, 501. Rickets inRats. X. Fasting Tetany and Phosphate Tetany.

9. Marriott, W. M.> and Howland, J., Arch. Int. Med., 1916, xviii, 708. Phos-phate Retention as a Factor in the Production of Acidosis in Nephritis.

267


10. DeWesselow, 0. L. V., Quart. J, Med., 1922-23 xvi, 341. On the Phos-phorus and Calcium of the Blood in Renal Disease.

11. Hannon, R. R., Shorr, E., McClellan, W. S., and DuBois, E. F., J. Clin.Invest., 1930, viii, 215. A Case of Osteitis Fibrosa Cystica (Osteomalacia?)with Evidence of Hyperactivity of the Parathyroid Bodies. MetabolicStudy I.

Bauer, W., Albright, F., and Aub, J. C., J. Clin. Invest., 1930, viii, 229.Metabolic Study II.

McClellan, W. S., Hannon, R. R., J. Clin. Invest., 1930, viii, 249. MetabolicStudy III.

12. Wilder, R. M., Endocrinology, 1929, xiii, 231. Hyperparathyroidism:Tumor of the Parathyroid Glands Associated with Osteitis Fibrosa.

13. Hunter, Donald, Proc. Roy. Soc. Med., 1929, xxiii, 27. Hyperparathyroidism(Hyperfunction of a Parathyroid Tumor in a Case of Generalized OsteitisFibrosa).

14. Albright, F., Bauer, W., Ropes, M., and Aub, J. C., J. Clin. Invest., 1929,vii, 139. Studies of Calcium and Phosphorus Metabolism. IV. TheEffect of the Parathyroid Hormone.

15. Barr, D. P., Bulger, H. A., and Dixon, H. H., J. Am. Med. Assoc., 1929,xcii, 951. Hyperparathyroidism.

16. Aub, J. C., Bauer, W., Heath, C., and Ropes, M., J. Clin. Invest., 1929, vii,97. Studies of Calcium and Phosphorus Metabolism. III. The Effects ofthe Thyroid Hormone and Thyroid Disease.

17. Binger, C., J. Pharm. and Exp. Therap., 1917, x, 105. Toxicity of Phos-phates in Relation to Blood Calcium and Tetany.

18. Tisdall, F. F., J. Biol. Chem., 1922, liv, 35. The Influence of the SodiumIon in the Production of Tetany.

19. Salvesen, H. A., Hastings, A. B., and McIntosh, J. F., J. Biol. Chem., 1924,lx, 311. Blood Changes and Clinical Symptoms Following Oral Adminis-tration of Phosphates.

20. Greenwald, I., and Gross, J., J. Biol. Chem., 1925, lxvi, 201. The Excretionof Calcium, Phosphorus, and Magnesium after Injection of Calcium Chlo-ride, Sodium Phosphate, or Both.

21. Orr, W. J., Holt, L. E., Jr., Wilkins, L., and Boone, F. H., Am. J. Dis. Child.,1924, xxviii, 574. The Relation of Calcium and Phosphorus in the Diet to

the Absorption of these Elements from the Intestine.22. Bauer, W., and Aub, J. C., J. Am. Dietetic Assoc., 1927, iii, 106. Studies of

Inorganic Salt Metabolism. I. The Ward Routine and Methods.23. Fiske, Cyrus, and Logan, M. A., To be published in the J. Biol. Chem.

First described in a paper by Hamilton, B., J. Biol. Chem., 1925, lxv, 101.Calcium Method.

24. Salter, W. T., and Farquharson, R. F., To be Published. Observations on

Urinary Acid and Ammonia Excretion.

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R. F. FARQUHARSON,W. T. SALTER AND J. C. AUB 269

25. Sjollema, B., J. Biol. Chem., 1923, lvii, 271. Studies in Inorganic Metab-olism. II. The Influence of Crude Fibre and of Protein upon Calcium andPhosphorus Metabolism.

26. Farquharson, R. F., and Tibbetts, D. M., J. Clin. Invest., 1931, x, 271.Studies'of Calcium and Phosphorus Metabolism. XVIII. On TemporaryFluctuations in the Level of Calcium and Inorganic Phosphorus in BloodSerum of Normal Individuals.

27. Salter, W. T., Farquharson, R. F., and Tibbetts, D. M., To be Published.The Relation of Acid-Base Balance to Phosphate Metabolism.

28. Farquharson, R. F., Salter, W. T., Tibbetts, D. M., and Aub, J. C., J. Clin.Invest., 1931, x, 221. Studies of Calcium and Phosphorus Metabolism.XII. The Effect of the Ingestion of Acid-Producing Substances.

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