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Select Committee on Health Minutes of Evidence

Memorandum by British American Tobacco

THE TOBACCO INDUSTRY AND THE HEALTH RISKS OF SMOKING (TB 28)

UK INDUSTRY RESEARCH

63. In the 1950s studies were published suggesting that smoking was associated with an increase in the incidence of disease including lung cancer and bronchitis. The UK tobacco companies responded by supporting research. In 1954, a group of companies, including British American Tobacco, on the advice of the Minister of Health, made a substantial grant to the Medical Research Council ("MRC") to undertake further research into the relationship between smoking and various diseases, in particular lung cancer and more generally into the possible causes of such diseases.

Tobacco Manufacturers' Standing Committee

64. The volume of research worldwide into smoking and health increased rapidly in the following years and, in 1956, British American Tobacco, Rothmans and other leading UK manufacturers established an organisation, the Tobacco Manufacturers' Standing Committee ("TMSC"), with the following mission:

"To assist research into smoking and health questions, to keep in touch with scientists and others working on this subject in the UK and abroad, and to make information available to scientific workers and the public," (TMSC, First Annual Report, TMSC, London, p 4, 1957).

65. In addition to sponsoring research by independent scientists, including the funding already given to the MRC, the TMSC monitored and reported on research in the smoking and health field, and published the first in a series of Research Papers, a survey of smoking statistics (which went through several editions) (Todd G F, "Statistics of Smoking", TMSC, London, (2nd edition), 1959).

66. The grant to the MRC supported research in the following fields: the epidemiology of lung cancer; the chemistry of tobacco and tobacco products; biological studies to identify experimental carcinogens; atmospheric pollution studies; and studies of other possible factors in the aetiology of lung cancer, including genetics. Among the researchers supported by the grant were Professor Sir Austin Bradford Hill of the MRC Statistical Research Unit; Sir Ernest Kennaway and Professor Blacklock of St Bartholomew's Hospital; Dr C M Fletcher of the University of London (a co-author of the 1962 Royal College of Physicians' report on smoking and health) and Professor Clemo of the Nuffield Department of Industrial Health (TRC, "Review of Past and Current Activities", TRC, London, 1963).

67. Independently of the MRC grant, the TMSC funded smoking and health-related research by many independent scientists, including Professor Sir Alexander Haddow, FRS, of the University of London and Chester Beatty Research Institute, and financed research at the University of Exeter, which conducted analysis of the chemical fractions of cigarette smoke.

68. On 1 January 1963, the TMSC changed its name to the Tobacco Research Council ("TRC") in order to reflect its increasing role in smoking and health research.

Harrogate

69. The most significant project undertaken by the TMSC was the construction, in 1962, of purpose-built bio-assay laboratories at Harrogate, Yorkshire. The tobacco manufacturers built these laboratories "to contribute to the development of acceptable and quantitatively reliable tests for measuring the biological effects of tobacco smoke" (TRC, "Review of Past and Current Activities", TRC, London, p 4, 1963). This research was to be carried out under the direction of Dr T D Day, who joined the TRC from the University of Leeds. Pharmacological laboratories were also under construction at Harrogate, where research on the pharmacological effects of smoking would be carried out under the direction of Dr Alan K Armitage.

70. "Working hypothesis": The biological research carried out at the Harrogate laboratories between 1962 and 1974 (when the laboratories were sold to Hazleton Laboratories Europe) was an effort on a major scale to elucidate what the TRC called their "working hypothesis". In short, this hypothesis was that tobacco smoke affects the respiratory epithelium by direct contact, producing changes which, in some smokers, lead eventually to lung cancer. The aim was to identify the chemical compounds giving rise to the biological activity of tobacco smoke and investigate factors in cigarette design which could modify such activity. "Biological activity" can be defined as a measure of the ability of a substance to produce a response in a biological test system, eg whole animals ("in vivo") or cells in culture ("in vitro").

71. Mouse skin-painting: In 1953, Dr Ernst Wynder and co-workers in the United States had demonstrated that it was possible to produce epidermoid cancers by the application of tobacco smoke condensate to the shaved backs of mice (Wynder E et al, "Experimental Production of Carcinoma with Cigarette Tar", Cancer Research, 13(12):855, 1953). The Harrogate laboratories employed mouse skin-painting as its main assay to assess the biological activity of tobacco smoke. It should be clearly understood that the purpose of the Harrogate main experiment, as it came to be called, was not to discover whether tobacco smoke condensate could produce cancers in animal test models. That it could do so had already been amply reported in the published scientific literature. The objective of the programme was to identify the chemical constituents of tobacco smoke primarily responsible for the mouse skin tumorigenicity of tobacco smoke condensate, and to investigate cigarette design modifications which might reduce the specific tumorigenicity (where "specific" tumorigenicity is defined as tumorigenicity by weight of condensate). From the outset, it was not clear that a direct inference could be drawn from the effect of painting very highly concentrate smoke condensate applied to the back of the mouse to any effect of whole, fresh tobacco smoke on the human respiratory system. Nevertheless, as the TRC observed:

"while one cannot necessarily apply to the human lung conclusions which have been drawn from animal experiments, nevertheless if several different lines of research with experimental animals all lead to similar conclusions, the probability that the results may have some relevance to the problem of human disease is increased" (TRC, "Review of Past and Current Activities", TRC, London,p 8, 1963).

72. Initial findings from the mouse skin-painting programme were published by Dr Day in 1967 (Day T D, "Carcinogenic Action of Cigarette Smoke Condensate on Mouse Skin: an Attempt at a Quantitative Study", British Journal of Cancer, 12:56, 1967). He reported that a high proportion of the tumorigenicity of cigarette smoke condensate was contributed by non-volatile components of the neutral fraction of smoke. The Harrogate laboratories set out to test more refined chemical fractions of smoke condensate.

"The objectives of the fractionation research have been to concentrate the mouse skin tumorigenic compounds into single fractions, to identify the main groups of these compounds and to develop chemical methods for assaying them" (TRC, "Review of Activities, 1967-1969", TRC, London,p 21, 1970).

73. In addition, the mouse skin-painting test was used to assess the effect of smoking parameters (eg the number of puffs taken per cigarette and the frequency, duration and volume of each puff) on tumorigenicity, and to compare the tumorigenicity of condensate from cigarettes exhibiting a variety of different design features.

74. The aims of the mouse skin-painting programme, and Dr Day's results, were discussed with eminent scientists including Professor Alexander Haddow, Sir Charles Dodds of the British Empire Cancer Campaign, Dr G F Marrian of the Imperial Cancer Research Fund, Sir Max Rosenheim, President of the Royal College of Physicians and Dr C M Fletcher. The significance of Dr Day's research was also discussed with the then Minister of Health, Sir Kenneth Robinson, and the Chief Medical Officer, Sir George Godber.

75. Results of mouse skin-painting programme: Despite years of effort, the attempt to identify beyond a certain level the specific chemical fraction of tobacco smoke in which mouse skin tumorigenicity resided was unsuccessful. By 1970:

"the progress of the work is shown by the finding that the major primary mouse skin carcinogens of cigarette smoke condensate can be concentrated into a single fraction representing only 0.2 per cent by weight of the condensate and that the major co-carcinogens or promoters can be concentrated similarly in a fraction representing about 0.4 per cent by weight of the condensate. This might make it possible eventually to identify compounds responsible for these effects, and thus to establish a chemical index of tumorigenicity. But great caution is necessary as these small fractions still contain many constituents and the separation techniques are working near their limits. Consequently, it is possible that the knowledge of smoke condensate, though greatly increased, will not be sufficiently precise to be used effectively as a chemical index. In this event, it may be concluded that this work has been taken as far as it profitably can". (TRC, "Review of Activities 1967-69", TRC, London, p 8, 1970).

76. These misgivings proved to be well founded and, by 1975, the fractionation work had been abandoned (TRC, "Review of Activities 1970-74", TRC, London, 1975). To this day, there is no consensus among scientists as to which specific chemical compounds in tobacco smoke are responsible for the increased incidence of lung cancer and other diseases observed in groups of smokers compared to groups of non-smokers. For example, in a recent article in "Carcinogenesis" it was stated that:

"So far, no clear cause-effect relationships have been established between individual or classes of compounds from tobacco smoke, and their effects on induction of genetic damage in human cells though smoking-related DNA damage was found at enhanced levels in target tissues and oral mucosa of smokers . . ." (Yang Q et al, "Cigarette Smoke Induces Direct DNA Damage in the Human B-lymphoid Cell Line Raji", Carcinogenesis, p 1769, 1999).

77. The mouse skin-painting results taken as a whole gave no clear guidance on any product modification strategy more effective than reducing overall dose. In other words, the Harrogate results were consistent with the view that, on the hypothesis that cigarette smoke affects the respiratory epithelium by direct contact, the most prudent course for the tobacco companies would be to make available cigarettes with reduced yields of smoke. This the companies were already doing. Whether the availability of low yield cigarettes would result in a lowered risk of smoking-associated diseases among their consumers could, of course, only be determined by long-term epidemiology.

78. Other biological research: In addition to the mouse skin-painting programme, many other lines of research were pursued at the Harrogate laboratories. TRC scientists developed a system for exposing laboratory animals to whole fresh smoke in an inhalation bio-assay. Like other workers in this field they were unable to develop this procedure into a useful assay for tobacco smoke carcinogenicity, because of the very few, if any, lung tumours found in exposed animals. As the US Surgeon General reported in 1982: "Attempts to induce significant numbers of bronchogenic carcinoma in laboratory animals were negative in spite of major efforts with several species and strains." (US Surgeon General, "The Health Consequences of Smoking: Cancer", p 218, 1982).

79. Various in vitro tests were also used at the laboratories to investigate other kinds of biological changes brought about by smoke exposure, and to look at the efficacy of filters in preventing or reducing such changes.

80. Nicotine research: Alongside biological research aimed at elucidating and reducing the possible health effects of smoking, the pharmacological laboratories at Harrogate investigated the pharmacological effects of nicotine. Dr Armitage and his team focused, in particular, on nicotine's effect on brain activity and the release of neurotransmitters, such as acetylcholine; the absorption, metabolism and excretion of nicotine; the effects of nicotine on behaviour and performance in laboratory animal models; and nicotine's effects on blood pressure. Dr Armitage and co-workers published more than 20 papers in scientific journals, including Nature and the British Journal of Pharmacology. These papers provided a significant contribution to the body of published scientific research on nicotine pharmacology, and have been cited by the US Surgeon General and others (eg US Surgeon General, "The Health Consequences of Smoking: The Changing Cigarette", p 46, 1981; "The Health Consequences of Smoking", p 203, 1986; "The Health Consequences of Smoking: Nicotine Addiction", p 38, 110, 407, 1988).

81. Publication of Harrogate research: The research at the Harrogate Laboratories was undertaken by scientists employed by the TRC, under the supervision of Dr Day, and the research directors who succeeded him. The details of the programme were overseen by a series of sub-committees of the TRC consisting of tobacco company scientists and external consultants with expertise in the relevant areas. The main results of the Harrogate programme were set out in a series of reviews of activities published by the TRC (TRC, "Review of Past and Current Activities" TRC, London 1963; TRC, "Review of Activities 1963-66" TRC, London 1967; TRC, "Review of Activities 1967-69" TRC, London 1970; TRC, "Review of Activities 1970-74" TRC, London 1975), as well as in papers published by TRC employees in scientific journals.

82. The mouse skin-painting programme at Harrogate was wound down, having been taken as far as it profitably could; without this large scale, labour intensive work, there was more space at Harrogate than was needed, leading to some redundancies and under-use of the laboratory space. Discussions with various research organisations were held in an attempt to provide Harrogate with a broader basis of work. In 1974, the TRC negotiated the sale of the laboratories to Hazleton Laboratories Europe Limited, a UK subsidiary of the Hazleton Laboratories Corporation, Virginia, USA. Hazleton continued to retain many of the former TRC scientific employees, and smoking and health-related work continued to be carried out for the TRC, under contract at Harrogate, for a number of years after the sale. The work at Harrogate also helped inform subsequent work by British American Tobacco aimed at exploring modifications to the product that might make it "safer".

TRC Sponsored Research

83. In addition to the extensive research mounted at the Harrogate Laboratories, the TRC continued, throughout the 1960s and 1970s, to provide funding for independent scientists to undertake a myriad of research projects related to smoking and health. We have been able to trace more than 400 publications in scientific journals supported by this funding, and it is likely that there are many more. It is possible in this memorandum only to give a broad indication of the scope of this activity. Among the areas in which the TRC supported research were: the psychological and pharmacological effects of smoking; the effects of smoking on the cardiovascular system; the association between smoking and non-malignant respiratory diseases; biological testing of tobacco and tobacco smoke; research on smoking motivation and behavioural aspects of smoking; and a variety of epidemiological studies. Among the institutions where workers received funding, were: The Marie Curie Memorial Foundation; The Institute of Cancer Research; Guy's Hospital; St George's Hospital Medical School; The University of Aberdeen; The Royal Post Graduate Medical School at Hammersmith Hospital; The University of Birmingham; The University of Southampton; The Tavistock Institute; The University of Cambridge; The Midhurst Medical Research Institute; The Cardiothoracic Institute; St James University Hospital in Leeds; The Royal Brompton Hospital; The Royal Free Hospital; and AEA Technologies at Harwell. Grantees were responsible for the conduct of their research and the decision whether to publish.

84. The tobacco companies commitment to joint industry research into smoking and health has advanced scientific knowledge of the subject, and the published results of this research have long been available as one of the resources on which the Government and its advisers can draw as a basis for public health policies aimed at consumer protection.



© Parliamentary copyright 2000	Prepared 28 February 2000