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K*B UNIVERSITY OF SAN FRANCISCO INSTITUTE OF CHEMICAL BIOLOGY 24 February 1982 u'rst, 'Y:^..D. Distinguished University.Professor ( Ec:eritus ) HARNEY SCIENCE CENTER SAN FRANCISCO. C.ILIFORNIA 94117 465/666-6415

464 UNIVERSITY OF SA: K*F UNIVERSITY OF SAN FRANCISCO 1NSTITLTE OF CHEMICAL BIOLOGY S'jyTEl«ffNP OF AR'IItt'R FURST, Ph.D. As a citizen and a resident of California since 1919, I applaud Congress= Waxran's continuinq efforts to imQrove the healt: of the Am-ican people. His mncern is certainly appreciated. I question, r.cwever, the sci- entific basis of his proposal (H.R. 4957) to amPS:d the Public Health Service Act and the Federal Cigarette Labeling and Advertising Act. As the attached copy of my curriculum vitae shcws, I hold the only Distinguished University Professorship (FYneritus) at the University of San Francisco. I am the Director (EZneritus) of the Institute of Chemical Biology (GSF), and I have been a professor of pharmacology at Stanford U:.iversity School of Medicine and a (visiting) clinical professor of pathology at the College of Physicians and Surgeons of Collarbia University. I am listed in Ykm's Who in the wbrld and Wor1d Who's SAw in Science. I an aconsultant (tesrQorary) to the world Health Osganization. In fact, I was a r.mber of the international working group that wrote IARC Monographs Vollure 2 and 23 on Evaluation of the Carcinogenic Risk of Chemicals to Hu:nzns. I an currently organizing an international conference on the toxicity and reproductive hazards of heavy metals. I also wnsult frequently with gove-:m-ental agencies and private industries on a variety of environmPntal health problems. I have read H.R. 4957 with great interest, for I have spent over thirty years in scientific research, auch of it studying tt:e questions of smoking and health. My original laboratory work on carcinogenesis antedates the first Surgeon 6ene.ral's Report on S9mking and Health. Over the years, I have studied the possible effects on animals of both whole smke and various smoke eoitQoneats. I have also investigated the carcinogenicity of a wide variety of substances, particularly the heavy metals, and I have care_full.y HARNEY SCIENCE CENTER SAN FRANCISCO. CALIFORNIA 9411] 413/666664t5 INSTITI r,cnitored the wvrld literature on experimen- :zckground will help explain my ooncerns a: flat, dogmatic statements about a scientific with uncertainties. A Congressional finding that "cigz cause of lung cancer" inplies a scientific c telieve to be unwarranted. My skepticisn as ;a-cowledge of and first-hand experience wit sroke and lung cancer. For many years, cigarette sr,roke, with no 465 I tried to indu success, despite r.lachines available. Not only were my colleac other investigator who attelspted to induce 1 tion of fresh smoke also failed. --•-- - There have been a very small nttcb cancers occurring in experimPntal anunals dur Anyone attellpting to interpret these as show; cer rrust understand that animals, like htanan cancer even in the absence of any suspected c an investigator mist ask t.:.:self is whether ani.^ials are actually a result of the expes rodents have a fairly high spontaneous ra ttiamrs) and adenoma (noranalignant tiarors) de data on the reports of increased adenocarcir. have found no difference between the incider ani.rals and the normal baseline, spontaneous : H.1RNEl SAN FR. 4i5/666-•

465 Page 2 UNIVERSITY OF SAN FRANCISCO INSTITLTE OF CHEMICAL BIOLOGY •:d i- ay _ty :tle in snt on tly ive :ies :ve.r of ites ious aide Illy cronitored the world literature on experiml;ntal czscinogenesis. Perhaps this background will help explain my concerns abcut Ii.R. 4957, which makes such flat, dogmatic statements about a scientific area which I kncw to be fraught with uncertainties. A Congressional finding that "cigarette sr.loking is the number one cause of lung cancer" inplies a scientific certainty that I, as a scientist, believe to be unwarranted. My skepticisn arises primarily `_ran r.w ~ extensive knowledge of and first-hand experience with aniiral exr.erir,ients on tobacco sr,roke and lung cancer. For many years, I tried to induce lur.g cancer in animals with cigarette sroke, with no success, despite the r.nst sophisticated smaking machines available. Not only were r.ey colleagues a,^.d I unsuccessful, but every other investigator' who atterlpted to induce lung cancer in animals by inhala- tion of fresh smoke also failed. There have been a very small nurber of published reports of lung cancers occurring in expesimental animals during smoke inhalation experiments. Anyone atteitpting to interpret these as showing that smoki.r:g causes lung can- cer aust understand that animals, like hlaoans, do soontaneously develop lung cancer even in the absence of any suspected carcinogen. The key question that an investigator mist ask 1^:.self is whether any cancers that develop in his aaimals are actually a result of the experimental exposure. For exaaple, rodents have a fairly high spontaneous rate of adenccarci.oma (malignant tumrs) and adenoma (norztnalignant tumors) develoFsent. I have examined the data on the reports of increased adeswcarcinana in smoke-e»aroosed animals and have found no difference between the incidence reported in the experimental animals and the normal baseline, spontanecus rate. HARNEY SCIENCE CENTER SAN FRANCISCO, CALIFORNIA 94117 4151666-6415

466 Page 3 UNIVERSITY OF SAN FRANCISCO INSTITUTE OF CHEMICAL BIOLOGY The lung cancer cell type traditionally associated with hur.lan sanking is squazmus cell carcinotra. The spontaneous rate of this cancer is considerably lower than that of adenocarcinoma in rodents, but it too does occur naturally in these animals. There have been very few reports of a squatrous cell cancer in smoke-e•cposed animals, and generally the authors made no amrent on these findings. I assuma that they concur with me that they were seeing nothing more than spontaneous production. Q1e of the animal experiments that has received the most attention is that on beagle dogs conducted by Auenbach et al. 'ltoelve years ago, they claimed to have succeeded in producing lung cancer in their beagles, but because their experimental methods were seriously flawed, I consider their oonclusions to be unfounded. Because the Auerbach experiment occasionally resurfaces as virtually the only exaaple of a positive inhalationai study result, I feel collpelled to repeat scme of the criticisms of that study that I voiced in 1972. Any time this experiment is praised, there seems to be no smphasis on the fact that the dogs received the sanke through a tracheostana. This in no way resembles human smoking. Unless the pictures I have seen are wrong, the smke was initially forced into the lungs through the trachea by use of a puaQ! This was without regard to the normall respiration rate of the dogs. Further, several of the dogs died from infections, aspiration of foreign material, etc., which is unusual in a e.ell controlled experiment. 7his qer *> F+TM* has no meaningfvl relationship to the tnanan experience, and any reports of timiors should be oonside> ed in light of the fact that the wtperimental data were not made available to an independent panel for evalu_ . ation, as requested. Also, since beagle dogs do get lung cancer ypcetarveously, a discussion of this fact would have been useful to readers inte=ested in evaluating the Auesbach work. HARNEY SCIENCE CENTER SAN FRANCISCO. CALIFORNIA 94u7 4151666•6413 INST The design and conduct of ineanir a great deal of sophistication. I have proposals and reports in the past 30 years nu-ber of the experimental designs or the ~ental data do not stand up to rigorous sir.plest recz+i*,e++ents that is often over. litter mates the controls and the experimer same strain of mice, the animals' spontar: vary from one supplier to another; this c i.-iteipretation of the data. Thus, even i cne experiment, a replication using animal ::othing unusual. It is also extremely important tc i^.`.ectious diseases in the animals can ser even if the animals are suceessfully tre: For exartQle, c.e can't be sure what ef Ccnter.will's Syrian Golden hamsters had S'L^dlarly, the possibility that Auerbach '~Oncern. In my own work, I always try c-'3ecking them very carefully before begin: Later that my animals are not clean, I 35a.in with - animals. That is the only r. i.-uestation or infection will not affect t1- In slmtnaLy, based on my own z literature, I have concluded that no reL •`ava shown that the inhalation of cigarette '-cd that skin-painting experimeats are inar- 467 UNIVERSITY OF Sr HAR` 5AN 41.i/6,

an is es a .de :ey ut :ir 1y no :Ia. ire by 1he of at. 3nd the lu- cer 467 Page 4 UNIVERSITY OF SAN FRANCISCO INSTITUTE OF CHEMIC.IL BIOLOGY The design and conduct of ineaningful animal experimentation require a great deal of sophistication. I have reviewed a vast nueber of research proposals and reports in the past 30 years, and I can assure you that a large numbar of the experimPntal designs or the conclusions drawn frcm the experi- mental data do not stand up to rigorous scientific scrutiny. C3ie of the sitrplest re.rluirerents that is often overlooked is the need to select fron litter mates the controls and the experimental animals. Even with exactly the same strain of mice, the aaimals' spontaneous rate of tum.or appearance will vary fran one supplier to another; this can cause serious probler.Is with the interpretation of the data. Thus, even if positive results are obtained in one experiment, a replication using aninals fran a different litter may yield nothing unusual. It is also extrerely inportant to use "clean" ani.als. Parasites or infectious diseases in the an;mals can seriously affect excperi: ntal results, even if the animals are successfully treated before the experiment begins. For exanQle, we can't be sure what effect the parasite infestation in Donter.will's Syrian Golden hamsters had on his inhalation study results. Similarly, the possibility that Auerbach's beagles had lung worr.Is causes concern. In my oan work, I always try to avoid using unclean animals by checking them very carefully before beginning an experirent. If I discover later that my animals are not clean, I terminate the experiment and start again with new animals. That is the only way that I can feel certain that the infestaticn or infection will not affect the expe.rimental findings. In slmmary, based on my own research and familiarity with the literature, I have concluded that no reliable, reproducible animal studies have shown that the inhalation of cigarette sroke causes lung cancer. I might add that skin-painting experiments are inappropriate for studying the question HARNEY SCIENCE CENTER SAN FRANCISCO. CALIFORNIA 94117 415/666-6415

INSTITUTE OF CHEMICAL BIOLOGY of tobacco smoke and cancer. We mist insist that aninall experiments si.rulate, as closely as possible, the human experience - and skin-painting, as well as certain other experimental techniques, fail to mimic adequately human inhalation. Various groups convinced of smking's causal role in lung cancer develognent have attempted to ignore or explain away the negative results in animal inhalation studies. For eYar.ple, I was once challenged in a scientific meetinq about the mice I used in my sr,oke inhalation studies. The individual argued that this strain could not develop lung cancer, and that is why I failed. But this is not true, because c.e have doclaoented well the production of lung cancer in these animals. Over a period of years we published a series of papers describing our technique of instilling carcinogens in the lungs of mice, the sensitivity of various strains of mice to carcinogens, and the res- ponse of the animals to different hydrocarbons. Yes, developlrent of all histological types of lung cancer is =mmn in animals treated with various carcinogens. It is even possible to rate experimentally the potency of carcinogens as inducers of lung cancer. .: In expe.rilrnatal carcinmgenesis, replication by independent investi- -gators is essential to establish the validity of the findings. Other researchers have been successful in replicating my experirrnsltal production of lung cancers. For exacrQle, in the latest issue of Cancer Research (vol. 41), Henry, et al., published a eatQlete confinnation of my research. They used the same technique, strain of mouse, cheeiical, and reported the same time of lung cancer appearance. It is in this context of successful lung cancer lnduction techniques that the failures of smoke inhalation studies should be HARNEY SCIENCE CENTER SAN FRANCISCO. C.ILIFORNIA 94117 415/666•6415 469 I (on-go. UNIVERSITY OF SA . . - _ , lNSTIT In general, the major health cla_ based mainly on epidemiological studies. epidemiological studies can only point out s factor jsuch as sROkingJ and disease; they c, Yet, the findings in H.R. 4957 are stated a, all is proven. Thus, as a scientist with ov tory research, I must disagree with those : are overstaterpnts of the scientific Imcwle s'roking and health area. I heartily agree with the recoananc funded and conducted. Yet, I zrnist etiphasize very iirportant. Scientific ]mewledge (in thi. advances only by publication of both succesa have been troubled that so little infozmatior Surgeon General about the negative Pxper;,,,er area. A case in point is Dr. A. Wner's wvr a result of their exposure to cigarette smoke, cancer, but also lived longer! Yes, the Smking and Aea.ith "oollect, analyze, and c information is excellent if both positive reported. Qaly with this unbiased approach m the public in general be met. I feel calpelled official agencies has been Chgr3ctCT ?ed by hi , I am particti]arly distuxbed by thE Surgeon General Health Consequences of &r Predecessors, it often omits references to positions it has adopted. l+Ilzy the omissic HARNEY ; SAN FRW 4LiJ66664

t t r 469 Page 6 UNIVERSITY OF SAN FRANCISCO INSTITUTE OF CHEMICAL BIOLOGY In general, the major health claims against cigarette slroking are based mainly on epidemiological studies. From the standpoint of science, epideniological studies can only point out statistical associations betwee.n a factor (such as slroking) and disease; they cannot prove a causal relationship. Yet, the findings in H.R. 4957 are stated as causal relationships, as though all is proven. Thus, as a scientist with over 30 years experience in labora- tory research, I nust disagree with those findings on the grounds that they are overstateawsits of the scientific kncwlecge - all is not proven in t',.e s-mking and health area. I heartily agree with the recYSrtrendation that Irore research anist be funded and conducted. Yet, I mast emphasize that negative results can also be very important. Scientific kncwledge (in this case, of lung cancer causation) advances only by publication of both successes and failures. This is why I have been troubled that so little infoanation is given in the reports by the SZur,eon General about the negative experimental results in tce lung cancer area. A case in point is Dr. A. Wemer's hork which shcwed that hamsters, as a result of their exposure to cigarette smoke, not only failed to develop lung cancer, but also lived longerl Yes, the rern,;*ement that the Office on 9x.mking and Health "collect, analyze, and disse+;*+ate" smoking and health infoxmation is excellent if both positive and negative findings will be reported. Qnly with this unbiased approach can the needs of both science and the public in general be met. I feel ocapelled to say that past perfoanance by official agencies has been characterized by highly selective reporting. I am particularly disturbed by the latest (1982) Report of the Surgeon General Health Consequences of 8mokin . Like so mazly of its predecessors, it often anits references to material contradictory to the positions it has adoptPd. My the omissions? Wry should a goveriasent HARNEY SCIENCE CENTER SAN FRANCISCO. CAUFORNIA 04117 ' 4h/8666465

471 UNIVERSITY OF SAN FRANCISCO INSTITUTE OF CHEMICAL BIOLOGY doclaaent selectively present only that part of the evidence that supports its position? In general, this Report provides no nea informaticn that would make me change my mind about the lack of good scientific inforsation on smoking and health. I agree with the Report's reca:mendation that r.ajor research efforts should be devoted to elucidating the mechanisms of lung cancer developrnnt. At this point, we have a number of theories, not proof, and in many instances not very good theories. The writers of the Report assare that the case against cigarette saeking is provw, and that the lack of Imowledge about the mechanisms involved is only the finishing touch - not really essential to prove the point. I cannot disagree more strongly. Unlike the writers of the Surgeon General's Report, I believe that until we have that proof, any conclusions regarding causation are preaature. I disagree with the Report's discussion of the animall inhalation experi++p*+ts using Syrian golden hamsters (many of them conducted by __ y._ Daltetmrill, et al. ) A suamaty section of the Report says that "studies on t smo]ae inhalation with the hamster now appear suitable" for evaluating the •tusrorigenic potential" of cigarette smoke. This seems highly incxmpatib? e : 4 with the Report's earlier comment that "why these inhalation experimelsts with hamsters did not induce carcimna of the lung *e+aine to be elucidated." Lung cancer can be induced in hamsters, by using a variety of substances. A1so; ' t significant moounts of cigarette smoke do reach the hamsters' lungs. So don't the hamsters get lung cancer after exposure to tobacco smolae? HARNEY SCIENCE CENTER SAN FRANCISCO. CGLIFORNIA 94117 415(666-6415 " INST The 1982 Report concludes that _°ailed to induce lung cancer in animals, . research efforts in this area should rece inccnPrehensible. The animal data are si basically contradict the popular interpret ahy? we aust have good research to find oL I am not in any way advocating : ce.:.ed with presenting the best informatic ^egative. I am also very concerned that -ill are assigned j?Z federal law to smokinc -esearch on and atter-pted control of man• causes of disease. For exaaQle, this fec effect on efforts to clean up our eavixnn cars, and to remove the particulates and nc I have lectured throughout Califc =~cer sponsored by the American Cancer Sc 7el.ieve that the public is well infou:ed e:ers to as the "dangers of snnking." -:aqazine ad, and every billboard ad ca=ri =t~.ermore, the Amarican Lung Association - _-e "tarch of Dimes are continually funding -M;cing. I cannot agree, therefore, with '=E government spend even more time and ef: '=-ey are ignorant of all the warnings that :Pariy 20 years. it seems to me that the c UNIVERSITY OF S, H.1RN SAN F 415/6E

The 1982 Report concludes that inhalation studies have basically failed to induce lung cancer in animals, but then it reccurends that further research efforts in this area should recei~m limited priority. I find that incrnprehensible. The animal data are significant negative evidence. They basically contradict the popular interpretation of the epidemiological data. h7zy? We mist have good research to find cut. I am not in any way advocatirg smoking; as a scientist, I am con- cerned with presenting the best information to the public, both positive and negative. I am also very concerned that if all the diseases noted in this bill are assigned ~X federal 1aw to saol:.i.ng, there will be a severe decline in research on and atter.pted control of many lmown or suspected envirormental causes of disease. For exarQle, this federal law can orly have an adverse effect on efforts to clean up our enviy-onment, to continue steg controls ia cars, and to remwe the particulates and noxious gases in the atr,osphese. I have lectured throughout California in prograr.ls on the Hiol of Cancer sponsored by the Ar.r.rican Cancer Society. Such contact has led r.le to believe that the public is well inforr.ied on what the prearrble in H.R. 4957 refers to as the "dangers of smoking." Every package of cigarettes, every magazine ad, and evexy billboard ad carries the Surgeon General' s warning. Furtr>exanre, the American Lung Association, the Anerican Cancer Society, and the March of Dimes are continually funding radio and TV anncuncements against sunki-Tg. I cannot agree, therefore, with this legislative requirement that the goveznmeat spend even more time and effort to infor:n the public as though they are ignorant of all the warnings that have been broadcast over the past nearly 20 years. It seeaLs to me that the public is indeed well informed, and HARNEY SCIENCE CENTER SAN FRANCISCO. C.IUFORNIA 94117 418(666&6415

472 Page 9 UNIVERSITY OF SAN FRANCISCO INSTITUTE OF CHEMICAL BIOLOGY that perhaps they have sinply decided that they wish to make their con decision. I would prefer to have these millions of dollars spent on good research, and not on more publicity caupaigns. Again, I respectfully suggest that Congress should encourage good research; I have been advocating this for 30 years. If we had received ade- quate funding of good research years ago, then ma.zy of the questions raised today might have been anssaered. Science, not publicity car.paigns, will solve our problens. HARNEY SCIENCE CENTER SAN FRANCISCO. CALIFORNIA 94117 415/666-64i5 P:R SC`:AL: 1937-39 Teaching Assistant University of Ca: 1939-40 Teacher, Science ar Pacific Military 1940-47 Instructor, Chemis+ San Francisco Ci- 3orn Minneapolis, Minnesota, Ca:i:ornia, 1919. Married, four c ....jZA/:ION: Los Angeles City College 1 University of California 11 at Los Angeles (UCLA) UCLA 15 Stanford University 1s PRUFESSIONAL EXPERIENCE: I --- During World War I: California War T: College; Univers. 1947-49 Assistant Professo University of Sa; 1949-52 473 CURRICULUM VITAE C Associate Professo University of Sa: 1949-82 Research Associate Mount Zion Hospi 1952-61 Lecturer, Chemistr University of Sa 1952-57 Associate Professo (Medicinal Ch Stanford Univers