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Home , Atomic Energy Project, Polonium, Radium

BIOLOGICAL STUDIES WI'I'H ,

RADIUbI, AND

Edited by

ROBERT 1\11. FINK, Ph.D.

.4 s CCT I 2 1 t. C ! I 11 I c ;I 1 P I.ofes SOr of Ph y si olc,eira1 C he m i st r y . School rvf hledlci!ie. Vniverslly of C.ililornia at LOS Amrlrs: Research Chemist. Birminghanl \' et c r a r. s .4 d ni I n i st r 11i on H o sp11 a I, Van Suys. California F,irmer Iy A:sI>iar.t Prufrssnr of Radlolocy and Biophyslcs. Sch(~c.1Of hledlcinc and Denllstry, L'niversiiv of Rochester

Ne.*. York . Toronto . London MCCRAW- HILL' BOOK COMPA N+, INC . 1950 PREFACE

This volume is oiic of n series uhirh has: been preparedas a record of the resrnrrli uork di>ne under the hlanhattan Project and the Atomic Energy Coniinission. The Iianic hlanhattan Project was assigned by the Corps nf Engineers. War Department, to thr far-flung scientific and enginecritic activities which lndas their objective the utilizationof atumic enrrry for military purposes. In the attainment of this objec- tive. there -u.rrc many developments in scientilic and technical fields which are of Ernera1 interest. The National Nuclear Energy Series IManhattan Pro jcct Technical Section) is a record of these scientilic and technical contributions. as well as of the developments in these fields which arc being sponsored by the Atomic Energy Commission. The declassified portion of the National Nuclear Energy Series, when conipletcd. IS expected to consist of some 60 volumes. These will be groulwd into eight divisions, as follows: Divisioii I - Electromagnetic Separation Project Divisioii I1 -. Gaseous Project Division 111 - Spccinl Separations Project Division 1Lr - Plutonium Project Divisioii V - Los Alamos Project Division VI - University of Rochrstcr Project Division VI1 - - hlaterials Procurement Project Division VI11 - hlanhattan Project Soori aftrr the close of thc unr the hlanhattan Project was able to give its attention to rhc preparation of a complete record of the research work accomplished under Project contracts. Writing pro- grams were authorizes at all laboratorie.s, with the object of obtaining complete coverage of Prujtct results. Each major installation was requested to designnte one or more representatives to make up a , committee, which iva? first called the Editorial Advisory Board, and :ater. after the sponsorship of lhe Series was assumed by the Atomic Energy Commission, the Project Editorial Advisory Board. Thi? wade plans to coordinate the writing programs at all the iiistallations. and acted as an advisory group in all matters affecting the Project-wide writing program. Its last meeting was held on Feh. 9, 1948, when it recommended the publisher for the Series. 9.

VI1 viii PREFACE

Thc innips of t..’ Board members and of the installations which tlwy represented ;’re given below.

.) .4tr~niirEjlerEy Commission pul~licrind TPcnnical Inlorrnatiori Alberio F. Thompson Srrvirf Technical Information Division. Brpwer F. Boardrnan Oak Ridce Extension Office of Sew Tork Operations Charlrr; Slesser. J. H. Hayner. W.11. Hearon Rrook1,avcn National Laboratory Richard u’. Dodson Carbide h Cnrbori Chemicals R. E. Korsrneyer. W. L. Harwell, Corporation (K-251 D. E. Hull. Ezra Staple Carllidc X Chemicals Russell Baldock Corporation I Y-12) + Clintoii Laboratories ? J. R. Coe General Electric Company. Haniord T. u’. Hauli Gt-wrnl Elrctric Cornp3ny. John P. Howe Kiiollc Atomic Pouer Laboratory

tiel 1 ex Corporation John F. Hogerton, Jerome Simson, hl. Benedict Lo5 Alarnoc R. R. Davis, Ralph Carlisle Smith Sationnl Bureau of Standards C. J. Rodden Pluionruni Project Argonnp Sat iorial Latrora tory R. S. Mulliken. H. D. Young 1t)u.a Statt. College F. H. Spedding \It.dical Group R. E. Zirkle CAhl Laboratories : C. M. Murphy

Zlq’i!r. 6 U’rbster Engineering 8. W. Whilehurst CorpFration Lni\ rriity of California R. K. Wakerling, A. Cuthrie Cnivrrsily of Rochester D. R. Charles, M. J. Wantman --

PR E F .4 C E ix

hfariy difficulties were encountered in preparink .I unified account of work. For example, the Project Editorinl Advisory Board xas the first conitnittee ever org3::izcd with repre- srnlntirfc2sfrom every major instnilation of the Atomic Energy Projvrt. Compartmentsticn for security UASso rigorous during the war that it had been considered necessary to allow a certain amount of dupli- 'cation of effort rathpr than to permit unrestricted circulation of research information betueen certain installations. As ;i result. the writing programs of dirlererit installations inevitably overlap markedly in many scientific fields. The Editorial Advisory Board has exerted itseli to reduce duplication in so far as possible and to eliminate discrepancies in factual data included in the volumes of the NNES. In particular, unified Project -uide volumes have been prepared on Chemistry aw,on the Analysis of Project Matcrials. Nevertheless, the reader uill find many instances of differences in results or conclusions on similar subject matter prepared by different authors. This has not seemed uholly undesirable for several reasons. First of all, such divergencies are not unnatural and stimulate in- vestigation. Second. promptness of publication has seemed niore important than the removal 01 all discrepancies. Finally, many Pro- ject scientists completed their contributions some time ago and have become engrossed in other activities so that their time has not been available for a detailed review of their work in relation to similar work don€ at other installations. The completion of the various individual volumes of the Series hns 3150 been beset with difficulties. Many of the key authors and editors have had important responsibilities in planning the future of atomic energy research. Under these circumstances, the completion of this tc>chnical series has been delayed loiiger than its editors wished. The )lunies ;ire heing released in their present form in the interest 01 ,~~sentingthe material as promptly as possible to those who can make use of it.

The Editorial Advisory Board

. The blmhattan Project Technical Scrticn of the National Furlear Energy Series is intended lo bc a comprehensive account 01 the XI- entilic and technical arhievements of (he lliiited Stiles precrlm for Ihe dewlopmen1 of alornic enerpy. It 15 net intended 10 bc 3 detailed documentary record of lhe niakine of my inventions th3l happen lo be mentioned in it. Therefore. Ihe dates used in the Serit.5 should be regarded 3s a peneral temporal franw of relercnre, ra1hr.r than as establishing dates 01 conception of inventions, 01 their reduclinn lo practice. or 01 occasions of Iirxt use. H'hil? a rer5on3blc elfort has been made to assicn rredit fairly in Ihc NKES volumes. this ni.cy. in rrmv cases. be given to a proup ldcnlilied by thc name of its leader rXher than lo an individual who was an actual inventor. -. CXIVERSITY OF ROCHF:STEIi PR0.T ECT FOREWORD /

Th'e Unii'er.sit!. of Rocl;c.-ter h1;iiih;itt:in PI.CIJ~C~had its inception On .2pril 5, 1943, with thc appointment of Dr. Stafford L. Wari'en.* Pro- Iwsor of Radiology and Chairman rll 1h(* Dcpartment d Radiology at !lie University uf Rochester Scliocrl 01 hlvdicine and Dentistry, AS Con- -ult;int to the P,lnnllattan Eneiric.~rDi:lrict (Inter ns Chief of the Med- ical Scction). Uiidr~his guidnncc ;ind direction the local project was ,stnblished and its opcrnticmnl policirs formulated. On November 2, 1943, Dr Warren Uac: commicsirmed colunel in the Army Medical I\. orps. and the subsequent respcmsibilily for the Project was assumed 135' the present Director on Novernbvr 13. 1943. In ninny respects the atmosphere rJ! the uork w;is in marked con- 'rast to the academic freedom d n university environment. The re- Parch w:is frequently of npplicd r;ithc.r th:in of fundamental nature, :IioUgh the latter was by no mc;inc Inckinc. In addition to physical and ,piritual isolation from our :iccucton;ed cnnfrerps. we found ourselves wrrounded by n multitudi of security. .\rniy. governmental, and war- lanpoxer regulations, but the nnjvrit?. of tlrc personnel made the messary nicntal adjustments uithuul undue. h:irdship and with corn- qpndable re:isonahlenesc :tnd gwId Kr:ic(.. !itv infrequently we found (lese appnrent handicaps uorking I(. cur riiuta.il ndvnlitace. The orgnniz3tirIn of thr- Project x.I.. iil..c,ui:Gc. unusunl and. to a cer- :in extpnt. experimental. TIJ arcunipli-ii thc tn+k in the specified

lmc and ((1 utilize effectiyely expcrier.(.( r! ~vr~onii~.Imade scarce by r'tivlF demands of thr war. indlr.i(i3u.ii- '~~rt'placed iri positions lie I,, r capahi1itie.q could pi-oduce niasiniuni benefit tothe Project .. a wllcrle. To thi; end. ten autonomrus but niu~uallyinterdependent .ivisionh were eshlilished, whocp coorciinnti~~iiwas effected through . c Director's Office so that priori!ics mi ni.itcrial. manpower, and )nccntrnlion of effort could be chni:ncIrd ir. thr proper direction with ..Y shifting phases of the various prchleti;-. Ex1)eriments were dis- .4.~sedand organized on a cooperativl:- b,isis through J system of plaluiing sessions" in such a manlier thlil the Cspert opinion of par- ipating members of specialized divisions could make major contri- ,itions to the structure of many of the espcrinients. This procedure

e. 'Sow Dea:. of the Medical School, Cniversity of California at Los Angeles.

XI xii L'KR'ER51TY OF ROCHESTER PROJECT FOREWOR3

nlsn twnblpd the dii.::- of Pnthologg, Hcnintolopy, ;rnd Statistics to coordinate their 3. livities with other divisions so that they could aiialyzr properly thr inass of experimental data which niust, of neces- sity , I )ns c: through the i r respectiv P Inbo r ;I to r ies. It would be misleading to aver that this system of research proce- dure presented here was without fault and not beset by difficulties. It is not nn easy matter for an investigator to reconcile his ideas and personal ambitions with those of a group for a common objective, especially when frequently his entire training and previous progress havc been based upon individual achievement. Particularly is this true when he has not had the pririlegeof participating in the selection of his associates. The system, however, worked surprisingly well under somewhat unfavorable circumstances and is worthy of further exploration under peacetime conditions. It is impossible to pay proper tribute to the many individuals- scientific, technical, and nontechnical -who participated in this en- deavor. Neither can one, by reading the following pages, appreciate fully the ineiital and physical labor that went into the enterprise. Approximately two million man-hours were required to produce the research from which these volumes are derived. The Administrative Office wishes to express its appreciation to the Project pfbrsonnel for their confidence and loyalty; to the Uniyersity as n whole ior its support and cooperation; to the many Rochester industries and busiiiesses for the materials supplied and the services rendcrrd: to the Ared Engineer's Office for its aid in facilitating the conduct of the procrnni; to Dr. Ellice hlcDonald, Director of Thc Bio- chemical Research Foundation of the Franklin Institute, at Newark, Dei., for his cooperation in coordinating the research under his con- tract with that of Rochester.

Andrew H. Dowdy, M.D. Professqr of Radiolocv and Director of the University nf Rocnester Project, 1943-1947; now Profezsor of Radiology, School of Medlcine, Cnivurslty of Cali- fornia at Los Angeles

*. , VOLEME EDITOR'S PREFACE

This volume reports the experimental studies carried out by the Biological Chemistry Section of the Division of Radioactivity in the Manhattan Department of the Uiiiversity of Rochester. The excellent cooperation of other sections and divisions, as well as that of all the 'personnel of this section, in collecting the data and preparing the report is gratefully acknowledged. The general problem undertaken was a comparison of the biological effects of three elements. polonium, plutonium, and , which had the common property of with emission of alpha particles. Since the biological distribution and of plutonium were being studied exhaustively in other areas, the report on the work carried out here can be divided rather naturally into three main parts. Part I deals with the distribution and excretion of polonium; Part 11 discusses the distribution and excretion of radium; and Part I11 deals with the comparative toxicities of polonium, plutonium, and radium. The Manhattan Project reports on these subjects have been condensed and correlated, and, wherever feasible, pertinent data obtained subsequent to the writing of the original reports have been included in the body of the volume. In Part 111, however, the difficulty of reanalvzing each group of data in the light of subsequent findings was too great; therefore the toxicity studies are included essentially as they appeared in the original Project reports. Subsequent data obtained in the toxicity experiments are recorded and discussed in Appendix 2 to Chap. 8. The material presented in this volume is largely based on the following Manhattan Project reports:

Preliminary Reporl on the hielabolism of Polonium. Robert M. Fink and William F. Bale. M-1529. AUK.2: 19-14, Progress Reporl on the ketabolism of Polonium. Robert hl. Fink. hl-1551. &pi. 21. 1941. Progress Repor! on the htetabolisni of Polonium. 111. Tracer Studies an I'U.0 Human Subjects. Wallace L. Minio and Robeyt M. Fink. hl-1579. Nor. 11. 1944. hogress Report on the hleiabolism OC Polonium. K. Further InIravenous and Oral Experiments with Rats. Wallace L. hlinto. Robert M. Fink. Elizabeth K. Vittuni. and Alice Taylor Gorham. M-lbSS, Apr. 16. 1945. Polonium Lileralure: Summary bf Studies on the Physiological Behavior of Polonium. Hannah E. Silbersrein. M-1519. Junb 23. 1944. Inhalation of Volatllized Polonium by Rats. Charles P. Kimball and Roberl M. Fink, M-1811. Dec. 20, 1945. xiv 7 '0L U hl E ED IT0 11 'S PR E FA C F

!.leia!,c.:icm o( Pn!rwiunr. I. Tracrr C:udir.c in Tkr I c Hum3n Sub!, rIs Folluwiric I:i!rJvemws 1-r Oral .4c. iriistraric~ii. Haiifi,ili E. Siilvi dcrn. N'illi.inl li. Valenline. Johl: S. Laurence. aiid Ii )crt 51. Fink. bl-18?f. Frtr. 6, 1946 RJciiuni PoisnQiiic: .A Surv of thP Literature De;lliy u itti :hn To:.it.itv aiid ClrlalY>lisni of Aliscrbed Radium. Hanilah E. Silherstein. hl-l@i, 5Sa:. 25. 194i. Metabolisni cl Radium. I. Tracer Sludirc P:: nits after Iiitr3vfr.o~~Administralion. Hanr.ah E. Silbrrclein and Robert 31. Fink. hl-li39. .\US. 2. 19-15, Conparalive Intr3ve:ous Lethal Dose Pi!i>I Studir> for Poloniuni. Rddiuni 3nd Pluto- nium iri Rats. Georre A. Boyd. Robert hf. Fink. Georcc bl. Suter.and Roser hleicalf. 31-1878. June 1. 1046. ConipJralive Intr3venous LPthJl D!wj;e Slud\ of Radium. Pluloniurn. and Polmibirr in Ra!a uilh Cliniral. Palholocical. and Hpniatulocical OSservarioiis. George A. Boyd and Robert hl. Fink. hl-1902. July 22. 1946.

The three elements investieated proved to be very interesting ones for coniaarison studies in that they differ widely in their half-lives, distribution in thc. body, and rate of excretion. These differences appear to be reflected in their relative toxicities. The problem of loilg-term human tolerance to a variety of radio- active materials is one that is likely to become of increasing impor- tance. Even the most exhaustive studies of the tvpe reportzd here may be insufficient to yield a completely satisfactory answer to that problem. Such studies are basic and necessary, however, and should be well worth while even if they assist only in clarifying the general prc,blem of the toxicity of radioactive substances.

Robert M. Fink

...... Project Foreword ...... si Volume Editor's Preface ...... xiii

.ling ones .ilf -lives, PART I. DISTRIBUTIOS AND EXCRETION OF POLONIUM ,fferences Introduction...... 3 a>f radio- By H. E. Silberstein I s inipor- 1.t.d here CHAPTER 1 vr to that General Alctiiod Used in Polonium Distribution and :id should Excretion Experiments ...... 7 t? general By A. T. Gorham. R. hl, Fink, C. P. Kimball, W. L. Minto, H. E. Silberstein. E. K. Vittum, W. F. Bale, T. Enns, and E. L,.Alling :.I. Fink CHAPTER 2 Polonium Distribution and Excretion Experiments with Animals...... 35 By H. E. Silbcrstein. W. L. Minto, R. M. Fink, G. .4. 3oyd, R. G. hfetcalf, W. Mann, C. P. Kirnball, and A. T. Gorharn

CHAPTER 3 Studies of Polonium Metabolism in Human Subjects 122 ...... !. By H. E. Silberstein. W. h'. Valentine, U'. L. Minto, !< J. S. Lawrence, R. hl. Fink, and A. T. Corharn

PART 11. DISTRIBUTION AND EXCRETION OF RADIUM I I

1 1, CHAPTER 4 i.:. Historical Background ...... 0. 157 'i , i By H. E. Silberstein I .I :I :I XV ti X \i CONTENTS

CHAPTER 5 Genernl Illethc !s Used in Iladiutn Dlstribution an(' Exc ret E ... ;,e rime nt s ...... 1 7 6 By H. E. Sillwrstcin

CHAPTER 6 Radium Distribution and Excretion Studies with Rats ...... 179 By H. E. Silberstein

PART 111. TOXICITY OF POLONIUM, PLUTONIUM, AND RADIUM IN RATS

CHAPTER 7 Pilot Studies on the Intravenous Lethal Dosage of Poloniuni, Plutonium, and Radium in Rats ...... 211 By G. A. Boyd, H. E. Silberstein, R. M. Fink. A. Frenkel. W. L. Minto, R. G. Metcalf, G. Casarett, and G. M. Suter

CHAPTER 8 Simultaneous Studies on the Intravenous Lethal Dosage of Polonium, Plutonium. and Radium in Rats ...... 295 By G. A. Boyd, A. Williams, W. L. Minto, D. V. Tiedernan, R. M. Fink, G. Casarett, and R. G. MetcalI

Appendix ...... 405 Indes ...... 407 Chapter 3

STUDIES OF POLONIUM METABOLISN IN HUhlAN SUBJECTS

It seemed desirable to have some data on th.e human excretion c poloiiiuni after the administration of known doses in order to obtain correlation with the more extensive data on rats. Inasmuch as it wa not poscible to determine accurately the amount of polonium alread present in laboratory personnel or to rule out the possibility of sub sequent accidental exposure of persons working with polonium, suc personnel were not suitable subjects for excretion studies of thi type. Accordingly, the general problem was outlined to a number o hospital patients with no previous or prohhle future contact with po loniuln. Oi the group uho volunteered as subjects, four men and on1 woman were selected for the excretion studies outlined below. The group ranged in age froin the early thirties to the early forties The polonium was admiiiistercd intravenuusly to the first lour sub. jects and orally to Uie lifth.

1. ISTIMVENOL!S STCDIES

By H. E. Silberstein, I!'.N. Valentine, W. L. Minto, J. S. Lawrence, and R. AI. Fink Case-- 1. A total of 22.6 microcurie (0.3 niicrocurie per of body weight) of poloiiium was adiiiinisterr;d intravenousl) to subject 1, a male patient being treated for generalized lympho- sarcoma. The polonium was adininistered in 10 1111 of sterilized isc tonic saline at pH 7.6. hi order t? determine as accurately RS possible the amount actually administered, a second 10-1111samplr of the solution was iiiiiiiediatc>ly drawn into the syringe used for thr injection and was expelled into aa solution at approxiniately tb rate used for the actual iiijectioii. The acid solution was set aside Io. subsequem radioactivity measurenient. This dummy-injection pro- cedure has been followed routiiwly and is quite necessary in huma.

I22 152 DISTRIUL'TIGB hhD EXCRETION OF POLOKIUM

cent n:r P than the difference bet..\een the original' aid final readings of the 1iiiqer. The finger was tlic*n rinsed in Clnrox (sodium hypo- chlorite' and the activity dropped to less tl;.:, 100 counts per minute. Unfortu; cltely the sodiuiii hypuchloritp inti.~i-f~.redwith the plating out of polonium on , :iivI tl~diiiouiit of +aiids in the solution pre- veiited the accurate reading of an evaporated sample, so that no check of the amount of activity in the second rinse solution was obtained except for proof that it contained more than 50 per cent of the orig- inal activity. It was not expected that anything less than complete ab- sorption uf the activity would give readable quantities in the urine unless the urinary escretion were superefficient, as was apparently the case in the stoniach-tube experiments with rats. Urine counts that tiad been running from 1 to 3 counts per minute per 24-hr col- lection before the experiment started dropped to 0.3 count per minute on the first day of the experiment and were therefore discontinued. AI one point during the experiment a drop of kerosene was acciden- tally spilled on the test finger, arid the activity after the kerosene dried measured the same as before. As was expected, the principal I conclusion from the experinlent is that absorption of polonium through 1: the human is too slow to be accurately measurable by methods involving the measurement of the amount remaining on the skin. If, as seeins probable, the niethod used is accurate to t 10 per cent, it niay be concluded that the polonium chloride present on the hands was absorbed at a rate not exceeding 2 per cent per day. 1 7. SUMMARY I. The rates of excretion of polonium by four liunran subjects, i1,jected ;. intravenously with 0.17 to 0.3 microcurie of poloiiium per kilogram of body weight, uere of the same order of magnitude as ,those obcerved in experiments with rats. During the first week after injectic. their iI average daily urine content was 0.1 per cent of the thearetical dose. In two cases, followed for longt?I- periods, this daily average :ell to about 0.06 per cent during the wc.xid week and to 0.03 per cent at 40 days. 011a single observation tAe urine collected on the seventieth i.'1 day aiter injection contained 0.02 per cent oi the theoretical dose. Polonium was eliminated in the at a level 10 to 20 times higher [ .. than in the urine. Fecal analyses on hro of the subjects shoued an 1. average daily output of 1.5 per cent of the theoretical dose during the 1 first week. The subject whose early fecal contents had been the low- i. er of these lwo continued to excrete amounts fluctua!ing around 0.8 'i per cent of the theoretical dose per day for another two weeks and then dropped to 0.6 per cent at 40 days and 0.25 per cent at 70 days. 1.. Evidence of the rapid disappearance of injected polonium from the blood stream was found by early sampling in two cases. Within the . STUDIES OF PO. CWUhl hlFT.XBOLISX1 IN HUAIAN SUBJ: ':TS 153

!ir:it ti;ilf I~aurthe avt.rnf;e total cii,culating poloniuin \vi, less than 5 ppr cent of the theqreticnl doce. The whole-blocd conc:litration at thr ei~dof 24 I;r iii ti:+ lour cases ayeraged 2 pi?* cent i the theo- rp'ic 11 d,.l+:e per liter. Each caw clme.etl a moderate rise, more ed in cells than in plasma, 11et:veen three and five days after in- , , .or,, the average at three days being 2.7 per cent of the theoretical dose Iter liter of blood. The values then fell gradually to about one- tenth of this level nt ;? days. The concentration in cells was generally tu-o or three times ereiter than in plasma, and somewhat greater in white Ijlood cells than in red blood cells. The uptake by cells was found to lx more rapid in the animal body than in experiments in vitro at room te in pe ratu r e. Following the ingestion of polonium in the one case studied, traces -%, of the material appeared iathe'r soon in the blood and urine, but the total abEorption was probably less than 10 per cent of the theoretical dose. The first blood sample, taken 1 hr after administration, con- tained 0.06 per cent of the theoretical dose per liter. After 48 hr the whole-blood concentraticin was 0.5 per cent per liter, and this very Kradually fell to a barely dctcctablc amount, less than 0.01 per cent of the theoretical dose per liter, 225 da:;s later. Plasma concentra- tion rose more rapidly in the early , but after the first week plasma and cell concentrations uerc similar. By the end of the first 2'2 hr the urine contained 2 :\' lo-' per cent of the theoretical dose, but the most rapid eyly escretion rate, 0.005 per cent per liter, oc- curred during the latter two-thirds nf the first day. Daily urinary excretinns uerr 5 to 7 pci c\'nt of tlir theoretical dose for 30 days after ingestion :utd then praduaily fell to 2 -' lo-' per cent at 230 days. Fecal elimination was i7 per text of the theoretical dose by the e,lc! Jf three days, averaged 0.26 per cent of the theoretical dose Pe lietween 10 and 30 days, atid finally fell to 3 Y lo-' per cent at .. .13ys. By this tirill> probabl) less than 0.6 microcurie remained in the body, giving lo-' microcurie per day in feces and 10'5 micro- jjer day in urine. A 11; ief experinient to test the a1)sorption of polonium through the huninn +kin ind,cated that it Wac. ait=orlled at a rate not exceeding 2 per, t.nt of the dose per day.

REFEHEKCES 1. J. C. Aut,, R. D. Evans, D. M. Gallagher, and D. M. Tibbels, Ann. Internal Mcd., 11: 1443 (19381. 2. A. C. Redfield and E. M. Brlght, Ani. J. Physiol., 65: 312 (19231.