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II!A1tVARD' MEDICAL SCHOOL BETH ISRAEL I-iOSPITAL DEPARTMENT OFM[DICIN[: Mailing Address: DIVIlIONOFR[fPIRATORTDIfHA3[i DART L. NUOtR. W1D-CNIRF DETN IsRAEL.NOi'PITAL 70ClROOItLINE AVENUlO3TON~,MAS.SACNURE'TT3 02210 1017.,, 73e~-2301 November 1!0,, 1978' Joel Gardner Enviro Control„ Inc. One Central Plaza . 11300 Rockville Pi~ke Rockvillo, Maryland 20852 Dear Joel, Relative to our meeting,with you and other representatives of Cnvi~ro Control, Inc, and the National Cancer Institute on Thursday„ November 2, 1978 (summarized in Appendix I), we are requesting ah extension of our contract for the hig,con inhallation bioassay for the effects of' high and low carbon monoxiLlie and high anal low n icotine content in tobacco, smoke on rates of atliero.gcncsis in the White Carneau l7igeoiu. In Appendix II' (attached) „ we have summarized in a, series of trLbllcs, the current status of our pigeon population and our projected needs to adequately answer the key questions relative to tobacco smoking and atherogenesis in this experimental model. Table I summarizes the current status of our pigeon cohorts,, and presentss the~ number of pigeons that 1':ravcbeen sacrificed for the h:igh: and 1'ownicotine cigarettes, with and without carbon monoxide supplementation, as well as the number of sham-smoked animals and shelf controlls studied. We appear to. have adequate numbers of'aniimals available for study for the six-month tilme period, and'probably adequate numbers as well at the three-month time period, alithoughiwe would like to supplement these entries with a few additional' animals. Table II presents the remaining population of pigeons available by exposure duration and treatment group. These are the male animals that are currently being smoked and can be fitted into any number of projected sacrifice schedules. Using the death tables and our best estimates of future predictable animal losses (Appendix III)~, which we submitted to you in greater detail in the October monthly report, we have summarized in Table III (Appendix II) the number of animals available inn each treatment group, as the study now stands. Iif we were to remain within, the restrictions of our current contract, ending November 30,, 1979, we would propose sacrificing these animals in accordance with the summary schedule presented in Table IV.This,wouldigive usbi~oassay points at periods of 0, 3, 6, 9', 12, and 15 months duration of exposure t; each of the smoking regimens. Idcallya we would like to enhance the numbers of animals at the three-month sacrifice and the nine-month sacrilfilce point, presented in Table IV. Indeed, we think it will be essential' to do so. As presented in our initial proposal, we anticipated having an eighteenth- month sacrifice point as well, for the last or "endIstabc"'of the experimental smoking regimens. As we discussed in ou meeting with you, and with the O consulitants,, we have some reasonably good insight intolthe natural history ~, and pathogenesis of atherosclerosis in the White Carneau pigeon maintai!ned' ~ on a high cholesterol diet, which will be best represented1by our shelf- p control animals. As theoretically projected in the ini'tial proposal, and ~' CA~

Joel Gardner Novcmlxcr 1''0„ 1978 C Page 2 as again presented in Figure 1(Appendiac IlI), experimental exposure too smoke of high and low nicotine content or high andilow carbon mono.xidee content may give us varying rates of atherogenesis in this model'. Inithat the model, particularly as it relates to smoke inhalation, is not. precisely defined, it is difficult to anticipate where the most significant differences in each of these experimental groups might potentially develop. I'1 think we are all in accord that it will not be evident, if it is going to occur, prior to the six-month sacrifice period. Our data would support that contention. We also know that after 18 months of a high cholesterol' diet, the animals wi1T be reaching,a relatively complete or "end stag,e'"' process of'atherogenesi:s, without any smoke treatment, as far'as deposition of' cholesterol plaques in the aorta occurs. No one knows what effect there will be on the coronary vesselis, and'at what point coronary atherogenesis in, that location,wi7;l be maximum. As suggested by Dr. St Clair from Bowman- Gray, with whom we are in accord, it may very well be that the point of' maximum separation will be between nine months of treatment and,15 months of treatment. If that is the case,, we would suggest that it will be extemely important to have the full 18 month experimental regimen completed, so as to have an end point to the development of'experimental atherosclerosis.. In fact, we would'like to add an additional number of shel'f-control animals that would be carriedlout even beyond this point, to the stage at which there is presumably relatively compl'ete obliteration of many of the coronary vessels and a d'eath rate from the cholesterol-induced' atherosclerosis per se'. In that context, then, we have presented what we feel will be the optimum exposure and sacrifice schedule in Table V' (Appendix II). The budget that we have presented (Appendix IV') for a six-month extension agreement to~our current contract would'permit this optimal scheduling of birds, both for the high cholesterol shelf controls and'for each individual smoking,regimeni„ at all of'the desired points of study. The professional salary component that we have requested is for an extension of the current efforts of eachiof'the key investigators for the additional six-month period. The technical budget presented is for'the support personnel„ at the current level of'funding,, for the six-month extension. As we discussed!in our meeting iin Bethesda, it will' greatly enhance the efficiency of'our endeavor if we can ad'd',„ for a two-week period, part time personneli to begin the smoking regimeniwith the new animals on an evening shift. As we have indicated in our progress reports„ the highest mortality in this model' occurs in this initial' two week adaptation period', and by undertaking, this component of our research with supplementary help on an evening shift, we will not compromise the ongoing,study and we will be able to maximize the input of new smoking,animals in the highest possible numbers. We are requesting,funding,for the purchase of 500 new White Carneau pigeons. As you know, there is only one major supplier of'these animals, both~for the United States and for several, foreign countries. It is virtually impossible to obtain male animals of'six months of age, and it has been necessary for us to purchase both male and female unsexed' younger animals and to house them for approximately 60' days or more in our own facilities before entering the males into the study. We will explore, at Dr. St. C1!air's suggestion, the potential fo our housing,these immature pigeons at

.Ioel Gardner November 10,.1978 8 II'agc; 3 13owm:n1-Gray i n olpu:n hens, rcrllrc iirp, the 12uid },;c.:tary cntr,u For c;rrc; ;ind' fGcdi ng ot' t@re animals IPrior to initi;rtiorr of the smoking, re,t;uiuens. 7flie acldiltiorr:rT suhples that we ld;rve rcqueyted are lrrojec'tc>d on tLreb:l.5is oE Clre cui'reut rate of our expenditures for these items, to cover the additional six- month period. We are allso rec{uesting fund'ing for one additional' set of pigeon cages, to house additional shelf-controls an.imals on a high cholesterol diet, that will be carried out for st-least 18 months of'study and preferably,, longer, to permit quantification of'the end stage processes and the naturall history of'atherogenesis in this model. The expenditures projected for the Charlesgate Animal Inhalation Facility are based' on our current rate of cost to the pigeon program at that location. We are alisoireqiuesting an additionaT $',2,000 in support for.travel. These traveli monies will be usedd for additional visits to Bethesda to consult in greater detail onithe program and to enhance our opportunity to make shared decisions. W'ewi1l also use these additional travel funds to visit the Iaboratories at the Bowman-Gray School of Medicine and the more experienced p rsonnel, working in this area. The amount of monies requested for the Harvard School of Public Health subcontract will cover the overrun generated by this group in the initial phases of the study, as was needed to perfect the pigeon-inhalat3on apparatus and smoke delivery systems. The only other major itcm ils a request for $2600 for consultation fees to a veterinary pathologist, and! $6,0001fon altechnicali salary for alpatliology technician on a part time basis over the remainder of the study. As we have indicated in our progress: reports, there are some striking changes occuring in the lungs of smoke- treated animals. Although the research design and current support of'the present contract has as its focus the study of tobacco smoking and atherosclerosis in the coronary andisystemic circulations, the concurrent development of alterations inithe pulmonary parenchyma, apparently as induced by exposure to tobacco smoke, should be thoroughly evaluated. This has not only importance relative to interpretation of'the results of studies onlatherosclerosis, but has inherent value of considerable potential significance on its own relative to the biologicalI effects of tobacco on the lung.. In summary, then, we are requesting additional funding to extend'our current contract for an additional six months, andiin so doing to supplement our current complement of'animaTs in the White Carneau pig;eon modeT for the study of'attierosclerosis by approximately 250 male birds. We have provided sacrifice schedules for optimum inclusion of experimental animals at the desired'sacrifice points, andiaddi:tional extensions of the workscope to cover new and potentially very important observations on the pulmonary parenchyma of tobacco smoke exposedianimals. We hope these projections meet with your satisfaction, as well as those of'the consultant to the program, and we will continue toldo our best to generate the information essential to understanding the role of'tobacco smoke in the potential modification of'atherosclerosis.. If I can be of any further hel'p toiyouiin evaluating these matters, please do not hesitate to call me directly. Sincerely, Z/ Gary L. Huber, M'.D.„ Chief Respiratory Diseases Unit GLH:mtc