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i "1jy Covvcir. Fort Touncco Ri:sL,utcu-U.S.A., INc. - •; ~,; I •:r! ~~., _ _1/ December 30, 1971 HEM0RAMU:d BLIDJECT: Why the Proposed Study Cannot Produce Heaningfu1 Results The prime considerations 1. The use of a tracheostoasr is much too artificial - traumatic in itself and utterly unlike real human smoking. 2. The smoke as received into the pulaons_ry system differs radically from that ordinarily inhaled by humans - a, the dilution by air is not controlled to duplicate h=an smoking. c. the temperature at which the smoke is inhaled is not controlled d, the degree of humidification is unknown 3. There is no measurement of the actual lung dosage of particulate material (tar) for co.parison with human er.perience. 4. The technical requirements for properly handling the fixation, sectioning, staining and ex=ining lu.-:rs for (1) emphfsenatous chanZes and (2) for neoplastic char.3es (especially tiny, incipient ones) are so different that these studies cannot realistically be conbined into one. (The same lung cannot be used for both purposes). b. the removal of ingredients by contact with the mouth area in human smoking is not ~ duplicated 5. small or incioient. Hence, if such lesions are to oe uscd as endpoints in a s„,:dy, they must be examined independently and blind by a large number (a panel) of pat3:olor,-ists who are in practice, highly experienced, relatively young. Because t7is point is so important, the task cannot be left to any one man or a small group of his intimates. Big nsaes of senescent or The art of patholor.,,5r is such that there vill always be serious disparities among pathologists in the interpretation of lesions that ray be related to neoplasm, esoecis!?•i Vhen these are THIS DOCUMENT SUBJECT TO CONFIDENTIAUTY AGREEMENT. CTR HN 0149Et8

1 T»>: CoUacIL Toit Toisncco I:iat:ARcic-U.S.A.. INc. -2- December 30, 1971 ~ ~~.. ~. . _ out-of-practice pathologists mean nothing here. Consensus is essential. I refer particularly to the traditional methods of pathology using visual examination of slides under the light microscope. I Hoxever, it is imperative now to use other techniques as well - behavior of suspect cells in tissue culture, electron microscope examinations, behavior on trans- plantation. Search for metastases is alva,ys most important. 6. Other types of observations, beyond ligbt-microscope pathology are necessary in these days - for example, biochemical and iasnunological changes. Such experiments must be continued throughout the normal life-span of the animals used if all the changes that might be significant are to be apprehended. No arbitrary time-schedule or cut-off date can be set since it might completely defeat the objectives. 8. Because of the importance of M'hole life-span observations, dogs may not be very suitable for this kind of study. Certainly, if dogs are used, short-lived breeds should be employed. ?doreover, the dw.onstrated i=pbrtance of using pathogen-free ani..als in lonQ-terra inhalation experiments i is a strong argument against the use of dogs since in-bred, pathogen-free animals are not generally available. The use of non-standardized animals requires that far larger numbers be employed for obtaining results that are even statistically significant. Moreover, the i=nunochemical reagents necessary for determining the status of the C-type LNA viral genome are not yet available for dogs. 7. 9. The plan does not show whether the necessary criteria are met for the production of "fresh, whole, normal smoke". (See attached meaorandua). Secondary considerations 1. The originally stated purpose of the proposed experiment was to answer the question: "Does the result of a skin painting experiment provide a valid prediction of the degree of haratLl effects when ciQarette smoke is inhaled daily by male beagle dogs?" Since the plan to include cigarettes made of reconstituted sheet has now been abandoned, this purpose has been lost since there is no information (that I knov of) about the relative effects of condensate from high nitrogen and low nitroEcn tobaccos on mouse skins. THIS DOCUMEMt SU8IECT TO CONflDE1VTIAUTY AGREEMEMT. CTR HN 0 1495*9

r available at the University of Kentucky for an adequate dog study? 4. Dd these investigators have enough space to handle the nuaaber of dogs needed? Tiii : CoL.xcis. F on Tonncco I:t:SE,kt:clc-U.S.A., I:vc. -3- December 30, ' . !7- 2: Separate observation of tirhole smoke inhalation versus inhala- tion of gas phase only, should be included in any such study. 3. Is there enough high nitrogen and low nitrogen tobacco 5. General consideration. Logistic limitations should not be allowed to influence the experimental design for a significant experiment. Better not do it if it cannot be done well. Robert C. Hockett THIS DOCUMENT SUBJECT TO CONfIDENTIAUTY AGREEMENT. 1971 CTR HN 014960