Large Animal Facilities at Ta-51

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This project will provide the facilities necessary to initiate pre clinical studies in large animals of biological characteristics and effects of negative pions relevant to their use for therapy of human cancer. I n addition, it will supply needed large-animal space to permit nominal expansion of the ongaing studies of radiation damage and recovery rates in dogs and monkeys and large-animal quarters for use of transient investigators when the WIMPF (Lo8 Alamos Medium Energy Physics Facility) becomes operational as a national research The original Health Research LaSoratory (TA-43), occupied i n 1953, was designed without large-animal facilities. a t the time was that LASL would csnfine its program elements i n animal radiobiology t o short-term acute o r semi-acute studies of radiation effects on small-animal species. directed t o programmatic investigations relative to effects of nuclear weapons, investigations of the acute radiation syndrome, mans of alleviating acute effects, and effectiveness of prampt massive doses Such studies were t o be of radiation for production of inca2a citation of flight crews and troops in military situations. ities was such that the experimental program was locked into specific The original design of animal facil - typs of sptcios and short periods

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By 1960 priorities and interests of the AEC and LASL had changed toward long-term effects of low-dose radiation and uptake, deposition, and excretion of radioactive materials involving use of large-animal largely by radioactive fallcrut from nuclear weapons and potential applications of fission reactors to meet expanding national power needs. In February 1960 a $ 325,000 addition tothe animal quarters was Change i n program emphasis was a result of prablcms created completed and immediately occupied for high priority genetic and radioisotope metabolic studies. 10,000 square feet gross space located as a single-story structure on the southwest corner of the original building. This addition included 5 monkey pens with outside exercise areas: 19 dog kennels with outside runs; 13 rodent experimental rcnms ; mouse, rat, monkey, and dog metabolic wards: feed storage rom ; cage-washing facilities : combined autopsy, surgery and treatment rcram, veterinarian ' s office, and locker This addition consisted of about roam for animal careta ' ars. This addition provided increased space for LASL and AEC mission-oriented animal experimentation. and constituted the first and only significant addition to the original building since its occupaacy i n 1953. In 1962 a satellite radiation exposure facility located ina remte area (TAZSI.) about 8 miles from the Health Research Laboratory underground octagonal structure t o house cobalt-60 exposure sources This facility consisted of an 1800 -square foot

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of 10, 100; and 1000 curies operated from a very s m a l l (144-square foot) control building located abaut 100 feet away, No cleaning or Iholding facilities for experimental animals were provided. facility was t o support radiation damage and recovery rate studies in large animals relevant to troop deployment and reuse in tactical nuclear warfare situations and i n civil defense operations. Because of inadequate large-animal cleaning and holding facilities in the type building (1720 square feet) and 20 gravel-surfaced dog runs were added at the exposure facility.This roughly doubled the dog-halding capacity for the biomedical research program. I n the Spring of 1970 modifications and another very modest (1,275 square feet)addition to the experimental animal quarters was . accomplished. The ns d if i cations and add it im resulted from a critical program review by the AEC Division of Biology and Medicine (May 14-15, 1968) and program re orientation in respmac to the A X ' S critic a high priority problem of effects of discrete high spzcific activity particles (specifically plutonium oxide) in the lung. The priority of this program element relates to environnental plutonium cmt mina tim and the probabilistic lung czncer risk Imposed on the public domain, The program review conunittee strongly urged that further animal w3rk at LkL be curtailed until facilities and care were improved and made compatible with " specific pathogen free" conditions while simultaneously recommending increased effort in animal radiobiology and strong reorientation toward thz high specific activity particle problem.

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mprovement of quarters to meet "specific pat b gen free" criteria entailed getting all animal roam entrances and services off main corridors of the building,setting up of an animal disease control and testing laboratory, provision of quarantine quarters,addition of a veterinary pathDlDgist and humid if i cation of all animal rooms. Program rc orient a tim toward the pl utm i ump article prDblem entailed further is al ation of animals containing plutonium, duplication of treatment and necropsy facilities,isolation ef a "hot" laboratory and histolagy working area and provision Df cont rsl led entrance and change rmrn to comply with personnel safety requirements and 'healtn physics surveillance for operations involving hazardous materials. The modification and addition resulted in a net gain of 3 offices and 4 small laboratories but a net loss of approximately 2,200 square feet of functional experimental animal space including three critically needed largo animal raoms. Tne 1,275 square foat add it im was.given over to a quarantine area, veterinary pathologist ' s office, separate necropsy room and ck i ef vet erin a ii an ' s office,essentially all required for cmp li ance with "specific pathogen free" criteria and p ravi ded n3net increase in space for prDgrammed research. Inthe Fall of 1970 a three-man review team headed by Dr. George Stapleton of the AEC Division of Biology and Medicine reviewed the LASL 'Mammalian Radiobiolagy Program element. the activity was very worth while and relevant to AEC-DBM needs but They concluded that the project on radiation damage and recovery rates i n dogs and

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sub-human primates should be imprmed by introduction of more animals into the study. Execution of this recommendation is limited currently by shortage of large-animal holding space. Within the next few mm th s the Biomedical Research Group may be expected to participate in an AEC-NCI program to investigate the - radio biological effects of negative pions from the Los Alamos Meson Physics Facility and their application to cancer therapy. Although operational funding for pre clinical and clinical investigations of pion applications to cancer therapy falls within the charter of NCI, provision of facilities and LASL based technical support would seem t o be the resp msi bil it y of LASL. If negative pions are t o be tried on human cancer patients at the earliest possible time,a step-wise appmach to the overall pr2gram, with overlapping time sequences fg rt ke variaus elements {see Fig. 11, must be taken i n the interest of ecm3my, efficiency, and assurance that n3 serious gaps are left unfilled prior t:, the beginning of patient therapy. The very fact that pions are an untried radiation necessitates considerable preclinical physical and radio bio lag ical observations t o make relatively certain that nb surprises exist and that the unfortunate early neutron thsrapy experience is not repeated. Programmatic preclinical dosimetry and radiobiology are required by the need to understand better the physical and biological properties of pions fr>r development of treatment schedules. The most relevant

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elements of the preclinical phase should consist of observations of ,pion M E and OER at high dose rates and under split and fraction a ted dose conditions, observations of early and l a t e radiation effects, and pathology i n normal and t u m 3 r tissues of animals and associated pion dosimetry and physical measurem.ents. It is important t o begin programmatic pre clinical studies directed tDward t'he requirements of the radiotherapy community at the earliest possible date if the need for such studies is not to delay the beginning of limited patient therapy and a definitive therapy trial. Much of the pre clinical pro gr mna tic pion radiobiology indicated abve will require mctre animal facilities for b3th small and large Measures t o provide a limited amount of tornparary small-animal space i n the existing Biomedical Research Laboratory by moving certain current functions (ICONS) t o Ten-Site are already un6erway. Sme of the pre clinical studies (depth dose distribution and pion-stopping region control and local fza tim, respmse of normal tissues, influence of tissue inhmmgeneities etc.) however, requires the use of an animal whse anatomy and bDdy size approximate that of the human. The miniature swine is t k animal of choice for such studies. The Biomedical Research Group has no facilities either at TA-43 or TA-51 for holding or experimenting with this species. specifically directed to providing such facilities. This project is

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Figure 1 shQws the Phases, Elements and T i k Frame of the Overall Program t o apply and test the effectiveness of negative pions in human cancer therapy. The elements of Phase I are completed on schedule, Phase 11 (Preclinical Programmatic Research and Development) will become time-limiting with respect t o the beginning of a human therapy trial. ment of experimental protocols and conventional radiation base lines are t o be accomplished in a short enough time frame to enable applications of negative pions to therapy of cancer patients at the earliest possible time the facilities covered by this project must be available. for accupancy n3 later than mid-January 1973 and earlier if possible. If the procurement of animals and the establish - For this campellins reason it i s uraently reuuested that the Droject be funded from FY-1972 GP? funds and construction beqin w i t h minimum The facility as planned is a bare minimum required t o perform the anticipated studies on swine. cwm it ted to becoming a national facility. over the nation who can obtain operational funding and project approval expect t o cme t o LASL where they will obtain beam time and supp mt facilities. Users Group, many of whom are anticipating submission of projects. ,The LAMPF, when completed, is Experimenters from all There are over 130 members of t h e Biomedical LASL does not have adequate animal facilities either for large or small animals, to accommodate these investigators. It is urged, therefore, that the facility covered by this project be so designed

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lrnd located that future add it ign s may be made at minimum cost. IIf provision of mare animal facilities (both large and small animals)- at LASL is not a part of future planning the concept of LAMPF as a national facility for Biomedical Users definitely will be a