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 smoke 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 rabbit~s, 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 Bio- Research Institute, Inc. A first smoking machine was designed and constructed by Richard Walton and began to be tested: by us on December 2, 1965. Exploratory studies with various modifications of the Walton machine continued to January 1967 when the first group of 100 C57BL/6 mice were subjected to chronic inhalation studies. These were replaced by 200 Millerton 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 1967. On November 1, 1967, a patent application for the smoking machine was filed by Richard Walton. On October 1, 1968, we suggested that "the time had come to decide whether or not the Walton reverse smoker should be universally accepted. " We stated that, base& 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 times 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 comment~ed that "the dilatat'ion of the alveolar spaces appears to be excellent, eo we judge that your technique for expanding the lungs by t'he intratsacheal instillation 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 lesser activity of fresh smoke was first noted by B'ernfeld 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 ontobacco smoke effects then proposed by Dr. Sim of Yale who wished to join us for this work. CTR declined to support this pr,,iect. - 1-

r . On February 26, 1970, two smoking machines were given Mason Research Institute for evaluation. On July 31, 1970, a renewal agreement was signed to cover the period from June 1, 1972 to May 31, 1973 for studies 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, 1970, differences in nicotine toxici'ty (by intraperitoneal 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 B'oard regarding the positive findings in our hamster sera for Sendai virus antibodies. Dr. Frank Rauscher wrote September 10; 1970, commenting on these antibodies: "For long term carcinogenesis studies it is reasonable to assume that these two viruses (Sendai and M adenovirus) should not'cause problems unless new evidence is uncovered to the contrary. " [On-0ctober 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 Sendai virus and that "false reactions were probably seen because of antibody against the sheep cells, not any particular anti'gen. " Thus the serious concern about: virus infections that influenced Council decisions mince 1970 proved to have no ecientific basis. ] I In September 1970 we were first made aware of a new modification of the Walton machine engineered by the Council for Tobacco Research and commented September 9 that we did not consider this modification to be workable. We citedifour major drawbacks of the machine. In March 1971 Dr. Guerin of Oak Ridge National Laboratories visited our labora- tories and was shown our smoking machine technology. On April 14, 1971, a report was made on nicotine (i. p. ) toxicity in ham- sters and on the effects of whole smoke at a 19. 2% concentrat'ion upon severali 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 1pve1 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 entirety with our own smoking, machine, not using the Council's horizontal n)Aification. On October 8, - 2-

1971, Mr. Hoyt for CTR approved a publication on "High Nicotine Toler- ance of Syrian Golden hiamsters. " u 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 in the lung, on mortality (which was low), on body weight, on organ weights, on triglyceride levels, on blood CO level and on isolated histological observations in the respiratorytraet. Samples for viral studies were sent,Dr. Huebner on April 21, 1972. On August 23, 1972, we suggested that studies on physiological parameters (breath sound profiles) be included in the evaluation of smoke- 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 the effects of sex, dose-response studies, determination of co-carcinogenic activity of smoke, studies in different lines of hamsters, including one line known to be resistant to a. c. polycyclie 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 18-22, 1973). In January 1973 a site visit by Dre. Hockett, Lisanti, Charles Sornmers 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 associates 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 Lauteretein and Lauterstein, lawyers to the tobacco industry, pointing out the indecisiveness of CTR on continuation of smoke inhalation experiments and his reasons why this appeared to him to be against the intereste of the cigarette industry. He was told that the first and essential step was the appropriate consideration by the CTR of the research which he was doing as well as of that he proposed to do. At'Dr. Gardner's suggestiony transplants of smoke- exposed larynxes into compatible hamster cheek pouches were made in February 1973 to -3-

04 allow survival of the larynx beyond the life- span of the originally exposed animaL I A paper by Dr. Homburger for presentation at' the March meeting of the Society of Toxicol'ogy was extensively rewritten by Dr. Hockett and Mr. Jacob who insisted that in addition a statement be insertied that "opinions expressed by the author are not necessarily those of the sponsor" (Ma-rch 20, 1973). On April! 23, 1973, support for the study of the usefulness of the golden hamster for smoke inhalation was extended f'or four months. On December 3, 1973 an abstract was submitted to Dr. Hockett of a paper to,be given at the FASEB meeting in April 1974 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 effects of cigarette smoking on the epithelium of the lary,nx and for studies of such effects upon certain lung parameters. A few days ago we were advised that the CTR' decided not to continue the studies on smoke inhalation in inbred hamsters. a - 4-