Tobacco Documents Online

Chronology of Events On December 4, 1964, The Council for Tobacco Research initiated an experiment on the effects of chronic exposure to tobacco amoke of populations of mice of various strains, to explore the effect of tobacco smoke when applied directly to the skin of mice as well as to various other organs of other species such as rabbits, rats or hamsters. It also was to support design and construction of a smoking, machine. This was financed by a grant of $350', 000 in five equal annual installments of $70, 000' each to B'io-Research Institute, Inc. A first smoking machine was designe& and constructed by Richard Walton and began to be tested by us on December 7_', 1965. Exploratory studios with various modifications of the Walton machine continued to January 1967 when the first group of 100 CS7BL/6 mice were subjected to chronic inhalation studies. These were replaced' by 200 Ivlil'lerton Swiss mice in May 1967 because of high mortality among the black mice. A great deal of work was done on acute toxicity of smoke of' various cigarettes in mice and a paper was published on this at a meeting of the Society of Toxicology in 196'7. On Nbvember 1, 1967, a patent application for the smoking machine was filed by Richard Walton. On October 1, 1968, we suggested that "the time ha& come to decide whether or not the Walton reverse smoker should be universally accepted. "' We stated that, based on our experience, we were ready to begin a new chronic exposure experiment. This was based on a review of data on 34' surviving mice exposed five t'imes per week for 55 weeks. Slides of these mice were reviewed by Loosli who called them poor and by Thelma Dunn and Harold! Stewart who commented that "the dilatation of the alveolar spaces appears to be excellent, so we'judge that your technique for expanding, the lungs by the intratracheal' instililation of fixing fluid is satisfactory. " From 1968 ,to 1969 the first' large-scale experiment for skin painting with native smoking,machine jet condensate was carried'out and the leseer activity of fresh smoke was first' noted by Bernfeld September 5, 1969. On November 7, 1969 the use of inbred Syrian~ hamsters was first sug- gested by us as part of a study of the effects of rodent viruses on tobacco smoke effects then proposed by Dr. Sim of' Yale who wished to join us for this work. CTR' declined to support thi's l r,.,iect. C ~..~ -1- .'M 0111 N ~1

On February 26, I'y70, two smoking machines we,( given Mason Research Instit'ute for evaluation. On July 31, 1'970, a renewal agreement was signed to cover the perio& from June 1, 1972 to May 31, 1973 for st'udies to determine the useful- ness of the golden Syrian hamster as model animal for inhalation studies. All the objectives of this study (except for gas phase inhalation) have since been met. On September 10, 11970, differences in nicoti'ne toxicity (by intraperit'oneal route) between hamster lines were reported. Also hamsters were found far less susceptible to nicotine than either mice or rats (all by the i. p. route). In August 1970 (letter of Dr. Hockett, August 11, 1970) concern was expressed by the Advisory Board regarding t'he positive findings in our hamster sera for Sendai virus antibodies. Dr. Frank Rauscher wrote September 10, 1970, commenting on these antibodies: "For long term carcinogeneeis studiee it is reasonablie to assume that these two viruses (Sendai and M adenovirus), should not cause probliems unless new evidence is uncovered to the contrary. " [On October 12, 1973, we obtained a report on a study initiated by Sam Poiley of NIH with IIT Research Institute concluding that no antibody was present in our hamster sera against Send'ai' virus and that "false reactions were probably seen because of antibody against the sheep cells, not any particular antigen." Thus the serious concern about virus infections that influenced Council decisions since 1970 proved to have no scientific basis. ]I In September 1970 we were first made aware of a new modification of the Walt'on machine engineered by the Co,uncil for Tobacco Research and commented September 9 that we did not consider this modification to be workable. We cited four major dirawbacks of the maa•hine. In March 1971 Dr. Guerin of Oak Ridge National' Laboratories visit'ed our labora- tories and was shown our smoking machine technology. On April 114, 197'1, a report was made on nicotine li. p. I toxi~city in ham- sters and on the effects of whole smoke at a I'i. Z o concentration upon several inbred lines of hamsters. The outline of an 18-month study aiming at 40 to 50, surviving hamsters in each group was submitted. Provisions were included for monitoring the CO level in blood! and data ~ were given on such levels during smoke inhalation. In August 1971 it' was decided to carry out this study in its entiret~v with our own smoking machine, not using the Council's horizontal Mrlifi'cation. On October 8, _ 2- `~~ i L

r-. I C C 1971, Mr. Hoyt for CTR approved a publication on~ "High Nicotine Toler- ance of Syrian Golden I-fametere. " On April 2, 1972, an interim report was submitted (with hamsters then having been exposed from 32 to 69 weeks): Observations were reported on clumping of macrophages inthe lung, on mortality (which was low), on body weight, on organ weights, on triglyceride levels, on blood CO level and onibolated histological observations in the respiratory tract. Samples for viral studies were sent,Dr. Huebner on Apri1IZ1, 1972. On August 23, 1972, we suggested that studies on physiological parameters (breath sound profiles) be included in the evaluation of emoke-exposed hamsters. This was never done. On October 10, 1972, we suggested new studies after completion of the current' work, including studies on the gas phase, studies on t'he effects of' sex, dose-response studiea, determination of co-carcinogenic activity of smoke, studies in different lines of hamsters, including one line known to be resistant to s. c. polycyclic hydrocarbons, increased rate of exposure to smoke, effects of different housing (singly), of the animals. In September (September 12), Dr. Hockett approved publication of "Pulmonary Histopathology of Hamsters Exposed to Smoke" (Society of Toxicology, March 118-22, 1973). In January 1973' a site visit by Drs. Hockett, Lisanti, Charles Sor¢uners and W. U. Gardner took place. In February the question of Sendai infection,(memo from Dr. Hockett, February 14, 1973), was again brought up. The virus was described by Huebner and associat'es as an interferon inducer which could thus have an effect upon chemical carcinogenesis. Since there was never any valid evidence of Sendai virus in our hamsters, this "concern" appears in retrospect most regrettable. On February 7, 1973, Dr. Homburger wrote to Mr. Jacob of Lauteratein and Lauterstein, lawyers to the tobacco industry, pointing out the indecisiveness of CTR on continuat'ion of smoke inhalation experiments and his reasons why this appeared to him to be again3t the interests of the cigarette industry. He was told that' the first and essential st~ep was the appropriate conaiderat'~ion by the CTR of'the research which he was doing, as well as of that he proposed to do. At Dr. Gardner's suggestion, transplants of smoke- exposed larynxes into compatible hamster cheek pouches were made in February 1973 to -3- `Z ~ ~ `_

I i allow survival of thClarynx beyond' the life- span of tRt originally exposed: animal. A paper by Dr. Homburger for presentation at the March meeting of' the Society of Toxicology was extensiveLy rewritten by Dr. Hockett an& Mr. Jacob who insisted that in addition a statement be inserted that "opinions expressed by the author are not necessarily those of the sponsor" (March 20, 1973)6 On April 23, 1973', support for the st'udy of the usefUlness of the golden hamster for smoke inhalation was extended for four months. On December 3, 1973' an abstract was submitted t(,, I)r. I-locket't of a paper to be given at the FASEB meeting, in April 1V74 on data from the final report: on this project. A complete final report was submitted to the CTR' on our inhalation studies concluding that' the Syrian hamster was suitable for studies of the ef!fects of'~ cigarette smoking on the epithelium of the larynx and Oor studies of such effects upon certain lung parameters. A few, days ago we were advised that the CTR dec 3ded nut to continue the studies on smoke inhalation in inbred' hamsters. - 4- `=