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« r TOBACCO INDUSTRY RESEARCH COMMITTEE 350 FIFTH AVENUE , NEW YORK 1, N. Y. Application For Research Grant Date: June 18, 1955 1. Name of Investigator: John H.'Heller) M.D. 2. Title: Executive Director 3. Institution & Address: New England Institute for Medical Reeearch Ridgefield) Connecticut 4. Project or Subject: Investigation of the relationship of surface charge of inhaled particles on their retention in the lung. yg 5. Detailed Plan of Procedure (Use reverse side if additional space is needed): Introduction The concern of the principal investigator for the past several years has been in the field of phagocytosis, particularly of electronegative colloidal particles by the reticuloendothelial system. Prior to the submission of this application, the entire lit- erature in regard to particles of colloidal size, such as cigarette smoke, was reviewed. This included publications of the United States Bureau of Mines as well as reports of the United States Public Health Service and publications from various other governments on particle inhalation through to clinical pneumoconiosis. A conference was also had with Dr. Ross Gunn of the United States Weather Bureau, who is the foremost authority on air-borne particles and their charge. (It was brought out at this conference that particles almost always reverse their charge when they become wet.) Apparently in no instance has anyone paid attention to or concerned themselves with., theor- etically or experimentally, the particle charge. It was felt by all with whom this was discussed that this might prove a fruitful avenue of investigation. (It is perhaps of col- lateral interest that workers in bauxite mines are among the miners who have no pulmonary involvement as a result of their profession. Aluminum dusts in the wet form are posi- tively-charged particles.) In the report of a single experiment on the inhalation in man of radioactive iron of colloidal particle size., it was demonstrated that almost all of the iron was eliminated from the lung after a period of circa four hours. The parti- cles involved had an electro-positive surface charge. A recent personal communication in regard to the work of Professor Policard in France indicates that experimental work there shows that the phagocytic action of lung cells in regard to specific particles is critical in retention of substances in the lung.

The possibility therefore presents itself that., should it appear that particular particle populations in smoke with a specific charge are those which) to a great extent, remain in the lung., an appropriate filter can be devised which can screen out particles with these charges. It is assumed that those particles rejected from the lung probably cannot be considered to be involved in any pathologic process., whereas particles of carbon and other materials with various chemicals adsorbed to them may cause a toxic or irritative reaction as a function of time. Procedure It is planned to make a variety of radioactive dusts of appropriate particle size. These substances will, for the first phase of the experimentation, be insoluble, and their charge will be determined electrophoretically in physiologic buffer. 'The first substances used will have metallic components and will be exclusively beta emitters. Animals of various species (mouse, rat, dog) will be allowed to aspirate radioactive dust through a tracheal canula. The entire operation will be carried out in a hermetically- sealed lucite glove box)rigged oxygen supply and C02 exhaust., and transfer boxes as safety precautions. Serial sacrifice of the animals will be made as a function of time after the aspiration of the dust., and serial micro-radioautographs will be made of the lungs. The locus of the particulate matter of different surface charge will be,assayed in this man- ner in order to determine whether or not it is rejected or if it is permanently held in the lung. In addition., gross estimates of the retention of isotopic dust in the lung will be made by ashing the lungs (or, in larger animals., portions of the lung)., and assaying the total radioactivity in a series of animals as a function of time. The gastrointestinal tract and contents will also.be checked for radioactivity as a measurement of particulate mat- ter which has been rejected by the lung and swallowed. The comparison of the negatively- charged and positively-charged particles will give indication of the degree of importance exerted by electrical charge. t

0 M ~ 6. Budget Plan: 000.00 $ 10 Salaries J Expendable Supplies 2,500.00 ~ Permanent Equipment 1,000.00 Overhead (15I°b ~ 2~025.00 Other 0.00 Total 15,525.00 7. Anticipated Duration of Work: One year. 8. Facilities and Staff Available: Participating staff on more than 50% time basis: R. Meier, M.D. - Physiologist L. Koerting, Ph.D. - Histologist J. Blizard, Ph.D. - Nuclear Physicist In addition to the staff mentioned above, other minor participants in the program will include H. Clark, Ph.D., Physical Chemist; R. Turner, Ph.D., Biochemist; and H. Van Collie: E ineer. Technic a ~re ofcourse~ available for all phases of the program. (Continued below.~ ~. ~'gditionaP Requ.~rements: The problem of making radioactive dusts of an appropriate particle size is a difficult, cum- bersome, and ofttimes dangerous procedure. To the greatest extent possible, this work will be farmed out. The cost for such service for specific dusts cannot be ascertained until a definitive order is placed. This may make some alteration in budget allocated for radio- active dusts. 10. Additional Information (Including relation of work to other projects and other sources of supply): One of the primary areas of interest in this Institute is fundamental work on the physio- pathology of the reticuloendothelial system. Work in other areas of phagocytosis is cur- rently being carried on with such substances as colloidal radiocarbon; colloidal CrP320~~ etc. The interrelation of reticuloendothelial activity, neoplasia, phagocytosis and in- fection, and metabolic dysfunction are currently being investigated by various staff mem- bers. 8. (Continued) This institution is equipped with complete isotope facilities including such instrumenta- tion as conventional scalers2 robot scaling equipment., windowless flow counters, flow Geiger tubes', liquid scintillation counters, monitors, etc. In addition to animal quar- ters, we have available for this work laboratories for nuclear chemistry, organic chem- istry, electrophoresis., chromatography,, and physiology. ctor of Project