Program and Abstracts of Papers to Be Presented at the Meeting Og the U.s. Atomic Energy Commission Advisory Committee for Biology and Medicine

Page 1

ABSTRACTS OF PAPERS TO BE PRESENTED AT THE I MEETINGOF THE U.S. ATOMIC ENERGY COMM , ADVISORY COMMITTEE FOR BIOLOGY AND MEDICINE .

Page 2

INFORMATION FOR VISITORS Sessions: All sessions of the meeting will be held in the seminar room of the Medical Research Center, 30 Bell Avenue. T h e Conference Desk is located in the lobby of Registration: Visitors will be registered at the Brookhaven Center, 23 Upton Road, on Wednesday evening, May 6, and at the Conference Desk in the Medical Center on Thursday, May 7, beginning at 8:30 a.m. Meals: Except for breakfasts, all meals for the participants of the meeting will be served in the Brookhaven Center. Breakfasts will be available at the Cafeteria, 15 Transportation: Laboratory cars will circulate in, the housing areas during the breakfast period to take visitors to the Cafeteria. While the meeting is in session transportation may be arranged by calling the Conference Desk, extension 300; at other times please call the Brookhaven Center, extension 2279 or 554. T h e Laboratory will provide transportation to planes and trains at the conclusion of the meeting; please sign up at the Conference Desk for this service. If you have any travel reservations to make or confirm, please fill out a travel information sheet (available at the Conference Desk) at your earliest convenience. Telephone Calls, Messages: Messages for visitors will be received at the Conference Desk or at the Brookhaven Center. The Laboratory number: area code 516, YAPhank 4-6262. The extension for the Conference Desk in the Medical Center is 300; extensions at the Brookhaven Center are 2279 and 554. Coin telephone booths for making outgoing calls are in the lobby of the Medical Center, at the Brookhaven Center, and opposite the Cafeteria. The cashier at 37 Brookhaven Avenue will be open on Thursday and Friday to cash personal checks up to 5550.00. In’Case.of Emergency After Hours, Call PoIice Headquarters, Ext. 41 1.

Page 3

Sodium, Genetics, and Hypertension. ................................. L.K. DAHL Clinical Studies on Cell Turnover .................................. E.P. CRONKITE Computer Applications in Medical Research..............J.S. ROBERTSON Biological Studies Using the Boron-Thermal Storage and Transfer of Information in Mammalian Cells.................................................. L.D. HAMILTON Simultaneous Tracing of Carbon and Hydrogen TOUROF THE HOSPITAL(Clinical Aspects ofthe Medical Department Program) .............................. V.P. BOND Enhanced Antibody Responses Elicited With Antitoxin Coinplexed With Either Tetanus Toxoid Studies of Iron and Vitamin B,, Metabolism............ L.M. SCHIFFER Neutron Activation Analysis in Studies of Homeostasis....G.C. COTZIAS

Page 4

10:45 Variations in the Sensitivity of Plant Taxa 4:OO Instrumentation and Health Physics Studies on Solid State Radiation Detectors.. Response of Monitoring Equipment Under Beam Conditions ......L.F. PHILLIPS and Advisory Committee Executive Session

Page 6

Sodium, Genetics, and Hypertension For some years we have been studying the role of dietary salt &e., sodium chloride) in human and experimental hypertension. These studies suggest that chronic excess salt ingestion can lead to high blood pressure in man and animals. Whether or not this is associated with sodium retention has long been a question and has been under prolonged investigation here, In our original studies to measure the difference between patients with and without hypertension was found. Subsequently in a small group of human subjects we observed that the biological half-life of Na” was longer in individuals with, than in those without, high blood pressure. Indirect calculations suggested, in contrast with our earlier observations, that this was because the hypertensive patients had more sodium in their tissues, Le., a larger sodium “pool.” Subsequently, however, similar studies in rats in which hypertension was induced only by salt feeding, failed to show (1) a prolonged biological half-life for an increase in total carcass sodium. These findings in the rat led us to a restudy of the problem in man. A series of 25 patients was studied, all under prolonged metabolic ward control. Measurements of the biological half-life of Na’? as well as total exchangeable sodium and potassium were made and the results essentially confirmed those found in the rats: as compared with non-hypertensive patients, neither a prolonged biological half-life for sodium nor an increase in the sodium pool was found with sufficient frequency in hypertensives to suggest that significant sodium accumulation in the tissues was a critical factor in the pathogenesis of the disease. In this respect, sodium may resemble carcinogenic agents which, having initiated a disease process, are no longer required for its perpetuation. In studies with rats we had observed that some salt-fed animals never developed hypertension whereas a few rapidly developed very severe hypertension followed by early death. These marked variations were interpreted to result from differences in genetic constitution. If this were true, selective inbreeding should result in two strains ofrats: in one, the members should develop hypertension from a salt intake from which the other strain would not. This has now been accomplished and i t is believed that the results have important implications for man. By mating, in successive generations, only those animals that failed to develop hypertension from salt ingestion, a strain (the Resistant strain) has been evolved in which large consumption of salt fails to influence the blood pressure significantly. By Contrast; from mating only animals that quickly developed hypertension from salt, a strain (the Sensitive strain) has been evolved that rapidly develops severe hypertension when exposed to the same salt intake that was so ineffective in the The genetic background t h a t controls the blood pressure responses to salt in rats reflected itself in another technique used to produce experimental hypertension, namely, compression of one renal artery. In this study, all animals were on a low

Page 7

Salt diet, yet those from the Sensitive strain developed much more hypertension than did those from the Resistant strain. Thus the genetic background seems to control the responses to two widely different factors employed to induce experimental hypertension. We suspect that this may hold for all experimental methods used to produce It seems reasonable to expect that similar genetic-environmental influences operate in man relative to the development of hypertension. We propose the hypothesis that hypertension may be triggered by the algebraic summation of a number of environmental factors, ip a genetically predisposed individual. Environmental influences operating on different individuals would be modified not only by dissimilarities in genetic composition of the respective individuals but by the intensity and duration of each environmental factor. Thus on the one hand would be the individual whose genetic predisposition to hypertension is so great as to require only minimal noxious environmental influence to initiate the disease; on the other hand there would be the person without predisposition who presumably never develops essential hypertension whatever the frequency or magnitude of the environmental insults; and somewhere in the middle would be the probably more common individual with only modest predisposition who is exposed to one or more environmental factors of such intensity or duration that hypertension results. Clinical Studies on Cell Turnover* Following the development and use of tritiated thymidine, H3TDR, to label DNA of dividing plant and animal cells at Brookhaven, the study of hemopoietic cell proliferation of human beings with normal and abnormal hemopoiesis was initiated in 1957. To date the study of blood cell proliferation kinetics in 28 human beings who have been given H3TDR or tritiated cytidine, H’CDR, has been undertaken. Patients have had the following diagnoses: brain tumor (2), carcinoma of the with myelofibrosis (Z), acute leukemia (5), chronic lymphocytic leukemia (8), multiple myeloma ( 2 ) , pernicious anemia (2). Much of the material collected still remains to be studied. Results on multiple myeloma, brain tumors, acute leukemia, and “steady state hemopoiesis’’ have been studied. Today the discussion will be limited to normal granulopoiesis, problems concerned with the flow rate through the marrow compartment, average time spent in each cytologic class, enigmata concerned with transition from the myelocyte to the metamyelocyte, transit through the maturation compartment of the marrow, release from thc marrow, and description of two probable means of loss from the peripheral blood - random and senescence. Speculation o n problems concerned with regulation of granulopoiesis will be AD. Chanana, P. Stryckmans, and Jose Rarnos have participated in these studies.

Page 8

Computer Applications in Medical Research Two large digital computers, the IBM-7094 and the Merlin, are available for general use at Brookhaven. Thk Medical Department has used these for a vari'ety of computing programs. In addition to routine statistical problems, the programs include analysis of tracer data in compartmented systems, gamma spectrum resolution, radiation dose in exposure of the head to neutrons, radiation dose in extracorporeal irradiation of the blood, and use in resolving the data obtained with the multidetector positron scanner. The tracer analysis program was developed by Berman at the NIH. Given data on the concentration of tracers in various compartments such as the blood, and including summing compartments such as the whole-body counts, the program computes the sizes of compartments and the rates of flow between the compartments in the assumed model of a biological system. - The gamma spectrum resolution program is used principally in connection with whole-body counter data. It makes it possible to analyze a gamma spectrum containing peaks due to several isotopes into its various components, so that even those isotopes contributing relatively small peaks can be qualitatively and quantitatively identified in a complex mixture. When the head is exposed to thermal neutrons, the radiation dose is attributable principally to the consequences of the N(n,p) and the H(n,y) reactions, with minor contributions from other reactions. If the neutron flux were uniform throughout the head, the geometry factors used for calculating the radiation dose from internallydistributed isotopes could be used, but because the neutron beam is rapidly attenuated, the geometry factors have to be modified accordingly. The program used considers the head as consisting of some 20,000 elements of volume. The radiation dose at 90 points of interest is computed by numerical integration of the contributions from the elements of volume, taking into account attenuation due to absorption in intervening tissues and due to the square of the distance. In extra-corporeal irradiation of the blood, only a small fraction of the total volume is irradiated at any one time. The irradiatd volume is returned to the circulation and mixed with the total blood volume. In such a procedure, some of the blood will be irradiated many times and some may not be irradiated at all. The computer program calculates the distribution of radiation dose in terms of the fraction of the blood volume that has made a given number of transits through the irradiation Th.e multid.etector positron scanner generates coincidence counting data in 178 pairs ofdetectors. Several programs have been developed in a search for the best one to use to translate the data into the coordinates giving the location of a localized sourcc ofactivity, as occurs when certain brain tumors concentrate positron-emitting isotopes. In addition to the digital computers, a n analogue computer designed principally for analysis of tracer curves is available. This instrument is useful at the model- , building stage and is used preliminary to the tracer analysis program on the digital

Page 9

Biological Studies Using the Boron -.Thermal Neutron Capture Reaction Neutron capture reactions furnish a means of pro?iding an intracellular source of high LET radiation that is subject to external control of timing. This modality has advantages in principle over irradiation with internally-distributed radioactive isotopes or high energy particle beams, and requires evaluation for potential therapeutic applications. Clinical trials with neutron capture therapy, however, have shown that further work at more basic levels is needed, and the current program is directed toward obtaining the required data on dosimetry and on biological effects at the animal and cellular levels. The bulk of the data referred to below have been obtained by Drs. Archambeau, Drew, Fairchild, and Robertson. Initial dose-survival curves using HeLa cells exposed to thermal neutrons in culture media containing 10 pg of Blo/ml of media suggest that the effects of the B’O(n,a)Li7irradiation on the proliferative capacity of HeLa cells are consistent with a “single hit” in contrast to the “multiple hit” reactions obtained from x ray and fromrthermal neutrons in the absence of boron. It was determined that a fluence of 5 x 1O’? neutrons/cm’ (30-min exposure) would produce a non-healing reaction in the skin of the pig, following an injection of 35 mg/kg of boron- 10. Sodium pentaborate was found to be poorly partioned between spontaneous tumors, the-blood, and other normal tissues. Achievement of a fluence of 5 X lo’? thermal neutrons/cm’ at a depth in tissue of 7 cm is not possible in the dog without severe damage to the intervening tissue and the bone marrow. The appearance of this effect even when no boron was administered points up the presence of excessive amounts of contaminating “advantitious” radiations in the thermal neutron beam. Gamma-ray intensities, thermal neutron fluxes, and fast neutron fluxes in anthropomorphic phantoms were determined using tissue-equivalent and threshold detectors. Measurements were made at the neutron port using different thicknesses of D,O interposed between the port and the reactor core. Depth-dose and depthflux curves were determined as a function of the thickness of thermal neutron absorbing filters in order to evaluate the penetrating power of the resulting “epiIt is expected that these studies will allow an objective evaluation of the possible role of neutron capture therapy in the management of malignancies. Biosynthesis of Collagen Hydroxylysine Hydroxylysine is an amino acid which, in mammals, occurs only in collagen. Experiments here at Brookhaven have shown that the only biological source of collagen hydroxylysine is lysjx. Labeled hydroxylysine, either fed or injected, does

Page 10

not find its way into collagen. Since animals lack the ability to synthesize any lysine whatever, it should be possible to study the biochemical pathway of hydroxylysine synthesis in systems uncomplicated by side reactions. As a first step in the study of the pathway we prepared lysine labeled on carbons 4 and 5 with tritium. Conversion of lysine into collagen hydroxylysine was studied in vitro in polyvinyl sponge biopsy tissue obtained from rats, and in vivo in chick embryos. Following incubation of the tissue with DL-lysine labeled in the carboxyl group with C“ and on carbon atoms 4 and 5 with tritium, lysine and hydroxylysine were isolated from hydrolysates of the collagen. In the in vitro studies the ratio of H3 to C” in hydroxylysine was about 80% of the ratio in lysine, indicating that in the conversion, only the one hydrogen atom replaced by a hydroxyl group is lost. At least two mechanisms of hydroxylation are consistent with this observation: a direct attack of oxygen on carbon 5, or a dehydrogenation between”carbon atoms 5 and 6, followed by the addition of tbe elements of water. Because of the results of other workers, the latter mechanism seems, at present, more likely. O u r present experiments are designed to test it. Storage and Transfer of Information in Mammalian Cells The theory of gene replication and mutation is based on the structure of deoxyribonucleic acid (DNA). These ideas are now being extended, e.g., the structure of RNA’s with various function in protein synthesis are …