Tobacco Documents Online

C f R f 3N 042295

BIO•RPSEARCH CONSULTANTS, INC. October lst, 1968 Robert C. Hockett, Pb. D. Associate Scientific Director The Council for Tobacco Research•U. S. A. 633 Third Avenue New York,. Nevr York 10017 Dear Bob: I should like to summariae our meeting of September 18th when Presy and you and I discussed ths present status of some of our researcta un- der our contract. C-159, as well as our grsnt, CTR-4. This letter covers the subject of our contract, C-1S9. ~ As you wili recall, CTR contracted with us to conduct experiments in var(ou:i'strains of mice on the effects of chronic exposure to tobacco anzoke, and on the effects of tobacco smoke when applied direetly for long periods of time to the skin of mice. For these purposes, we have designed a neav snaoking anaehine. Our last interim report to you on this work was dated June 7th, 1968. During our discussions, I brought you up to date on the current status of the smoking machine and on the results of exposure experiments. Speaking of the smoking arsachine, our prtsent version, as described In the report referred to above, is probably the final one (or very close to it), sinee it appears to fuliill most, if not all, of the reeluirements for such equipment formulated by CTR. We are open to any suggestions from the tobacco industry as to possible modifications, but we believe that the time has come to decide whether or not these machines should be universally accepted. In the event that those who have to make this. decision considered the machine now adequate, we are ready to begin -a tw ebrbnic axposure experime7at~ If ruch a d-ealston'wr:re not forttr-- coming, we should suspend this type of work until the universally ac- ceptable ptandard machine has been designed. 50070326 ~ - m CTR ~~ ~~~~

BIO•RESBARCZ•i CONSULTANTS, INC Dr. Hockett Page a October lst, 1968 The present model of the Walton machine is now being used by us for di• rect application of fresh toba.cco condensate to mouse skin. i I r 1 also reported to you on out last histological findings on 34 mice that had been avtehlns-exposed for 55 weeks (5 times per week), and oa i7 controls which had bsen placed In the macbine with cigarettes that were not lit. The salient histological features are hyperplasia and metaplasla of the bron- chisl epithelinta In a lair proportion of the mice tbat- have been exposed to smoke. Bronchitis and pneumonitis occur in smoke-exposed mice only in the same proportion as. seen in the controls. In addition, in the smoke- -exposed mice, 8 out of 34 +thowed bronchiolectasts ro.hich sras rather mark- ed aad which may have the samt underlying disease process as emphysenna, which we could not clearly distinguish In these mice. In my opinion. I must s/1Y that the mouse is not a suitable experimental animal for studies on empbysema because various degrees of emphysensa are visible In most mouse lungs thht are fixed by iatratracheal injection with neutral formalde• hyde. In this connection, it was decided that I should write to Dr. Loosli, requesting him to agree to review some of our slides and to tell us whether, in his opinion, our histological procedures are adequate. I have done this. .1te also discussed the possible inflttences of virus infestation in the Miller- =on mice upon the final outcome of our experiments, and that it was impor• tant to know the spectrum of serum viral antibodies in these mice. This i.nformit3on will be obtained from Mr. Sanks 'of Millerton Research Fari,a, Inc. If It is not available, we shall ask Dr. Huebner of N.I. H. to carry out virus studies on M.illertom Farm mtcs. We discussed the future pla=ins of this contract study and decided that we should, In any cas., delay the next chronic study until standard reference cigarettes from the Vniversity of Kentucky will be available. This delay will allow us to set up a multifactorlal experiment carefully designed to study the efiects upon the acute toxicity of smoke concentration, duration of exposure, frequeucy of eacposure and duratton%)f purge. 'rhis will deter• -mine those ronditions necessary for administration of the maximum toler- ated doses because the statistical likelihood of producing carcinoma with a doss rvhiah Is comparable to the one to which humans are exposed is re- mote, !t one assumss uauriae •usceptibility to be equal to that of man. In accordance with generally accepted methods of toxicology, one must re- eorr to higher (toxic or maximal tolerated) doses to increase the likelihood of positiva results. The multifactorial acute toxicity stadtes would serve to indicate which of the rariables In the annoke exposure technique are most significant In allowing to increase the maximum tolerated dose. Once we 50070327 CTR ~~ ~~~~'~1~`

BIOLRBSBARCH CONSULTANTS, INC Dr. Hockett Page 3 October let, 1968 have decided which are the most important factors, we could then test such factors in small numbers of mice from various etratns and perhaps find a. ,train that would be even more resistant to acute smoke toxicity than the Millerton ailce wbich, h.owwer, have treen qnite suitable for at least yearolong exposure at the level used by us. You poinRed oux tbat it would be desirable to carry out an experiment of chronic exposqre to gas phase alone to determine.ohether bronchial hy• perplasia aad metaplasia can be induced by gas phase alone. Since both of these changes have occurred after only 21 weeks of exposure to full smoke, such an experiment need not exceed in time about Z0 to 30 weeks. We discussed certain admi»istrative aspects of this contract. Yon point- ed out that within CTR, this contract was actually being handled as a grant. It appears to me that this may confuse your scientific advisors, as well as your adxn4nistrative personnel. They may not realiae that under this contract, we are conducting work planned specifically at the request of CTR, and closely monitored by CTR. Work done under contracts Is more expensive thaa that earried out under grants due to taxes and to different distribution between direct and indirect cost and, hence,.lo larger over- head for contract work. Therefore, any CTR money which is paying for contract work with Bio-Rssearch Consultants and on wbich we are paying taxes and carrying commercial overhead, must be considsred within CTR as entirely apart from grant-in-aid funds awarded to Bto-Research Insti- tute under which work io planned by us and published as a service to the publia. To establish a clear separation in thinking of these two types of support In our case is necessary to understand the difference in cost be- tween contract work and Rrwt-in-aid of research to other grantees who work exelusively under non»profit grants. I hope that you can discuss this further with your associsxes in administra- tion ia CTR. Allow me to tnank you again for the time which you so generously gave me. With best regards, FH:er cc:Dr. C. C. Little 50070328 Yours siacerely, m _- ~ Freddy Homburger, M. D. W ~ President and Director ~ C* * TR 1- 1 N 0 422 91 81.1