Biological Studies with Polonium, Radium, and Plutonium (First Edition)

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BIOLOGICAL STUDIES WITH POLONIUM, Formerly Assistant Profe.ror at Radiology !md Blophyslcs, School d Medlclae and Dentistry, School of Mediche, University d Califomla at New York Toronto. London McGRAW-HILL BOOK COMPANY, INC

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and statistics to that they could Le his ideas and in the selection xthy of further ated in thiu ento produce the tor of The Biote, at Newark, m a volume reports the experimental studies carried out by the g~logicalchemistry MOnd the Division d Radioactivity in the D.putmont d tho Unirorsity d Rochester. The excellent ~oopcrationd other IoctloLu and divbiow, aa well as that of all the prmnnel d this aection, in collecting the data and preparing the mprt ir gratefully acknowledged. he general probhm uu&rtakon waa a comparisonof the biological effect8 of three ebmeRt6, poloaium, plutonium, and radium, which bad the common property ot mdhactive decay with emission of alpha pnrticlem. Sac. the bio-81 dirtributioa and excretion of plutonium were baing rdudied axhau8Uvely ia dJmr are-, the report on the work carried out b r o can bo dlvi&d rather naturally into three main parts. Put I &a& with tha didributioa and excretion of polonium; Part II dtrcu8808 the didrh&m and oxrotion ad radium; and Part m &ala with the comparative toldcitier d polonium, plutonium, and d u m . Th4 Manhattan Project reports on these subjects have been condensed and correhted, and, wherever feasible, pertinent data obtained subwquent to the writlag d the original reports have been included in the body d the volume. In Part m,however, the difficulty ai nuulpriaq each group d &ta in the light of subsequent findings was too great; therefore the toxicity studies are included essentially as they w a r o d in tho original Project reporta. Subsequent data o b h e d in the tordcity ewrimenta are recorded and discussed in Thr W r l a l prcmnted in thir volume is largely based on the Cotloring YPnluttnn Project reports: Prgru lbport on t& Notabollrrn of Poloaluor. Rokrt M. Fink, M-1551, apt. 21, Polonium Literature: Summary d Studln on the gliologicrl Behavior of Polonium. tluuvb R. Slbersteln, Y-1510, lune 23, 1944.

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STUDES OF POLONIUM METABOLISM EN HUMAN SUBJECTS It seemed desirable to have some data on the human excretion of polonium after the administration d known doses in order to obtain a correlation with the more ex bn siv t data on rats. Inasmuch as it was not possible to dctermfne accurately the amount 02 polonium already present in laboratory personnel or to rule out the possibility of subsequent accidental tlrposure d persona working with polonfum, such personnel were not suitable subjects for excretion studies of this type, Accordingly, the gendrrrl problem was outlined to a number of hospital patients with no previous or probable future conbct with polonium. Of tb group who volunteered as subjects, four men and one woman were selected for the excretton studies outlined below. The group rangdin age from the early thirties tothe early forties. The polonium wob administered intravenously to the first four subjects and orally to the fifth. Case 1. A total of 22.6 microcuries (0.3 microcurie per kilogram of body weight) of polonium chloride was administered intravenously to subject 1, a male patient being trtated for gentralized lymphosarcoma. The polonium was administered in 10 ml of sterilized isotonic saline soludon at pH 7.6. In order to dttermine as accurately as possible the amount ;rctually administered, a second 10-ml sample of the solution was immediately drawn into the syringe used for the lnjtction and was expelled into an acid solution at approximately the rate used for the actual injection, The acid solution was set aside for cedure has been followed routinely and is quite necessary in human

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es of this id for the STUDIES OF POLONIVII METABOLISM IN HUMAN SUBJECTS 123 studies, in which the loss of one-fourth to one-half the polonium occurs durlng the sterilization d the neutral solutlon in the autoclave. In determining thc amounts excreted in the daily urine collections the total M y volume was measured, and a convenient aliquot (about 5 per cent d the total) waa taken, acidified to O.SN H+ with concentrated hydrochloric acid, and plated directly onto a silver-foil disk, which was read in an ionization chamber or alpha counter. The daily urinary excretion of polonium by the first subject and the concentration of polonium per milliliter of urine are given in Table 3.1 and shown grpphically in Fig. 3.1. Owing to an oversight the use of a glass uritlll for these collections was not specified, 80 that it is possible that this rrmkrlrrtorp patient used a stahless-steel urlnal and that the second, badriddcn, patient used a metal vessel. A subsequent check indicated that use of the metal vessel would result in the loss of less than one-tenth of the polonium in the specimen. Fecal samples were obtaineddaily from this subject for seven days after injection. Each sample was weighed, a suitable known volume ab 3N HCl was added, and the sample was homogenized with an electrically driven glass stirrer. Aliquots af each day's sample were digested and analyzed as described in Chap. 1. The total daily excretion through tbe feces and theconcentrattons d poloniumtherein a r e given in Table 3.1 and are shown graphically in Fig. 3.2. The concentrations of polonium in the blood of this first subject are also shown in

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STUDIES OF POLXlNNH WETABOWSM IN HUMAN SUBJECTS 125 -Case 2. A total of 11.3 microcuries (0.17 microcurie per kilogrun d body weight) of polonium chloride was administered by intravenous injection to the second male subject. This patient had acute lymphatic tion of the material. As in the case 05 the first subject, the dose administered was determined by means of a dummy injection through the same needle immediately after the ac-1 injection. h urh. Urb Wholablood pkau Bloodcdb The daily eaeretion d the concentration d polonium in the urine are shown ia Table 3.1 and Fig. 5.3. On microscopic examlMtlon the urine samples showed some red blood cells, and the sample taken during the f i r s t day in particular was very dark colored. As both the red cells and tha bile contained very much &@herconcentrations of polonium tbpn did the urine, the presence d small amounts d either may w e l l have raised the urine concentration beyond the range for This ptlent passed very small vnounts d feces, hut a single sample obtaimd one day after the injection contained 8 per cent of the theoretical &me per Uogram of fecal matter, a value similar b that found for the corresponding sample from the first subject. The concentration of polonium in the blood of subject 2 is also shmn in Table 3.2. An autopsy was performed urd tissue samples were taken about an hour after the death d this patient. The tissue samples were dues- and plattd out on silver foil, and their radioactivity was measured according tothe methods described in Chap. 1. The concentrations of polonium found in the various tissues, cxpressed aa percentages od the theoretical dose per kilogram of tissue, are tabulated in Table 3.3. The bile obtained from the gall bladder showed the highest concentration, being more than four times as high

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STUDIES OF POLONIUM METABOLISM IN HUMAN SUBJECTS 127 a reading SO per cent higher than the first sample. This increase of activity after standing indicated that, despite the seen$fngly adequate measures for the decontamination and segregation of glassware, the dorr pot kilfzrun heart digest had probably been stored in a contaminatad bottle. More stringent measures were instltubd threafter in order to avoid further occurrences of this sort. In any event, it aeemcd that in this human study, in contrast to the rat and rabbit experiments, the theoretical dose as determined by the dummy infection was probably a more accurate measure of the polonium injected than was the amount

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DBTRIBUTION AND EXCREnON OF POLONIUM recovered, an estimated from excreta and tissue analyses. For thb reason, and psrtrcullrly because the incowhncy between the theo. retical &se and the estimated recovery may have been due largely Tb.0rotk.l Dou for Subject 2 rrd aa Pore med Dore for l0-d.y Ewrimrafr rw! ? b o Rats ud a Rabbit errors in a very few tisaues,thc humnn data are left fn terms of percentages dtheoretical (dummy) dose without attempting to correct for retention or recovery.

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STUDIES OF POUlNNH METABOLISM M HUYAN SUBJECTS 129 The relative concentntlons of polonium in the tissues d man, rat, and rabbit errpressedon an approximately comparable basis are shown in Table 3.5. The data on percentage of theoretical dose per gram for subject 2 have been adjusted for the factor ob body weight by multiplying by Yioa of the body weight i n grams for comparison with the rat and rabbit data of Table 2.29, but, as stated previously, no corrections have been made for the estimated recovery or retention figures. The relative concentrations d polonium in the various tissues of subject 2 (Table 3.5) in general agree fairly well w i t h the comparable values for either the rat or the rabbit, perhaps agreeing some-

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DISTRIBUTION AND EXCRETION OF POLONIUM frequently with the rabbit. The human bile, liver, a d cell, and thyroid values are Lower ulyl those for either the rat or fie rabbit. Data on the amount of polonium in entire organs and Ussues (Table 3.4) show more differences because they involve the added variations due to differences in excretion and the differing sizes of the organs in the three species. ' It is obviously impossible to evaluate accurately the effect of the pirthologicai sfate d the human subject upon the distribution of polonium in his body, but some points seem worth mentioning. The possible effect of the kidney damage on the values of urlnary excretion hsls already been discussed. The principal autopsy findings were numerous petechial hemorrhages, cramming of the spleen and bone marrow with round cells, hyperplasia of the young lymphocytes in the lymph nodes, and confirmation of the jaundice and anemhnoted above. It seems possible that the Infiltration of mund cells might have lowered the spleen and bone marrow valuesfrom those found in a normal subject, although cause and effect might be reversed, as with the hyperplasia inthe Lymph nodes. Anemk would be expectedto reduce the polonium concentratha in blood because d the relatively high concentration ordinarfly found in red blood cells. The jaundice, although not especially interesting to the pathologists in this case, is perhaps of more interest in this tracer experiment on account of the very high concentration of polonium found in the bile. During jaundice the concentration of bile is reported to be particularly high in the liver, skin, muscle, and plasma. Xnasmuch as in these tissues the human subject had relative polonium concentrations considerably higher than did the rats, it seems possible that the jaundice contributed in some measure to the high values. Thus as they stand, the tissue data indicate a fairly close similarity betmeen the human, the rabbit, and the rat with respect to the distribution of polonium administered Intravenously, and it seems probable that a man in good general health would show an even closer similarity. H, however, the data on subject 2 show an essentially normal distribution of polonium in humans, then that distribution is quite favorable as compared w i t h that in the rat, for ?he human put a higher concentration of polonium into such relatively insensitive tissues as liver, skin, and muscle and a lower concentration into bone marrow, lymph nodes, pancreas, thymus, and thyroid. Case 3. Subject 3, a male patient with chronic myeloid leukemia, was injected intravenously with 10 ml of sterile physiological saline, pH 7.4, containing 12.0 microcuries of polonium chloride. The dose was equivalent to 0.18 microcurie per kilogram of body weight. The

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rat or the fect of the ytas in the jection and 80 mg % on the sixth day after injection, possibly indicating a mild disturbance in renal function. The excretion data from this case arc shown in Table 3.6 and in Figs. 3.4 and 3.5. The total daily polonium in the urine was fairly constant for several days after injection. It averaged 0.097 per cent of the theoretical dose per day for the first 18 days md fell to 0.02 per cent at 70 days, The polonium appeared in the urine as soon as 1 hr after Injection at a concentration as high as that s e e n two or three days later. From the 1st to the 18th day urhary concentrations varied between 0.04 and 0.09 per cent of the theoretical dose

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per Liter. The avenge daily fecal output dwhg the f h t 17 days was 0.71 per cent of the theoretical dole, neiLrly 10 times the urhe ~ 0 5 - tent. Although the 24-hr fecal excretion values show marked fluctuations, the concentration of polonium in the feces remained at a fairly constant level-between S and 10 per cent of the theoretical dose per kilogrvn for as long as 17 days after injection. By 70 days it had dropped to abut one-third the earlier values. Blood sampling for analysis w a s btgun 15 m h after injection. Because of this patient's high white count it was possible to follow the

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sys it had STUDIES OF POLONIUM Y(ETAB0LISM M RUHAN SUBJECTS 133 polonium content not only kr plasma and red cells but also in the white blood cells for more than tuoweelts a€terthe beginnin0 of the experiment. For this separation the 5-in1 blood svnple was poured into a conical 12-ml centrifuge tube and allowed to stand until the red cells settled to the bottom. Sedimentation was completa after 2% to 3 hr in the first few sunples,but later samples required 4 to 5 hr. The white cells, together with most of &e plasma, were then carefully pipetted into a second centrifuge tube, and the taro fractions were centrifuged for 40 min. Both hematocrits were tben recorded, and the plasma w a s removed from both tubes and combined for analysis. The samples taken at 3 and 5 hr after injection were left standing overnight

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total circulating plasma, and the red cells already showed a marked uptake of polonium. (See the discussion in Sec. 5 concerning the in vitro increase d the proportion of the polonium in the red blood cell fraction.) A portion of the cell uptake observed in the early blood samples probably taaL place in vitro while these samples stood in the test tubes for 3 to 18 hr. The plasma content rose by the fourth day to about 10 times the level at 3 hr and then gradually fell, so that by 70 days it was again similar to the 3-hr value. Red cells, with a concentration generally two to four times that d the plasma, contained about 2 per cent of the theoretical dose per liter during the second week after injection, but the contcnt &creased to about onetenth of that level at 70 days. White cella showed …