Joint Research by British Tobacco Industry

Sir Charles then describes the new tobacco toxicology laboratory at Harrogate, which was to be run jointly by tobacco companies in the United Kingdom through the Tobacco Manufacturers' Standing Committee (TMSC). In the course of his discussion, Sir Charles explains the BAT board's policy on the smoking and health issue:

The Board recognises that this problem must be tackled from two sides, the first being medical research on the origin of lung cancer and bio-assay on the biological effects of smoke, and the second being the composition of smoke and the possibilities of modifying it. The Board has decided that if this Company makes any significant scientific discovery clearly relevant to health it will share its knowledge with its co-members of TMSC and not seek to obtain competitive commercial advantage. The Board has therefore decided that they will whole-heartedly support TMSC to carry out and co-ordinate all research on smoking and health. TMSC will do this by itself carrying out biological work at its establishment at Harrogate and by sponsoring biological and medical work at Institutions. TMSC will depend on member companies for physical and chemical work [emphasis added]. {1102.01, p. 5}

While the BAT board made a commitment to share information on how to reduce cigarette toxicity with other tobacco companies rather than "seek[ing] to obtain competitive commercial advantage," there is no mention of making research information available either to the public or to public health authorities.

More important, as of July 1962, BAT was committed to cooperative investigations and product development when they were "health-oriented." A "health-oriented" product, as it would later be defined at the Hilton Head research conference in 1968, was one that reduced the actual hazard of smoking. In contrast, a "health-image" cigarette only appeared to provide a health benefit (see below). The fact that the company had decided to share any promising results with the industry as a whole strongly indicates that the company now realized that its products did, in fact, present a hazard. If the company regarded the evidence that smoking causes cancer as false, misleading, or inconclusive, it is difficult to see why it would have seen the possibility of a competitive advantage and adopted the policy that it did.

Sir Charles couches the rationale for conducting "health-oriented" research in the following guarded terms:

The central fact in this subject is that in sufficient doses tobacco condensate acts as a carcinogen when painted on the backs of mice, or when injected subcutaneously into rats. In sufficient dose it also acts as a co-carcinogen in mouse painting tests. On present evidence the amount of the known carcinogens in smoke are insufficient to make it plausible that these experiments could be extrapolated to support the view that smoking is harmful to human beings, but at least they serve to indicate a group of substances which require intense investigation and which, even if we do not know why, we would be pleased to see less of [emphasis added]. {1102.01, p. 7}

Despite this cautious attitude toward the implications of the mouse skin model, mouse skin painting had by this time become the test used by BAT to examine whether a particular manipulation of cigarettes reduced the risk of cancer. Indeed, discussion later on at this research conference demonstrated the hard-nosed attitude within R&D at BAT that the company would rely primarily on mouse skin tests in estimating the value of any maneuver to remove toxins from cigarette smoke. Mouse skin painting was, then, the definitive assay for cancer at BAT—even though, in public, the tobacco industry minimized the value of data from mouse skin–painting experiments. The public posture was that this model was not at all relevant to a determination of whether cigarettes cause cancer in humans.

The TMSC laboratory, which was to open at Harrogate on September 1, 1962, was to be capable of running mouse skin–painting experiments at twenty-five to fifty times the size of in-house efforts. Two thousand mice were to be used in the initial experiment, instead of the forty to eighty that were conventionally used. The start-up costs were put at

£250,000, and the annual budget was estimated to be £100,000. Research results of this and other studies were to be published as a matter of policy {1102.01, p. 33}. In determining the sample sizes to be utilized in the initial experiment, the planners had done calculations of how small a difference could be detected between the activities (i.e., carcinogenic potential) of different condensates. Sir Charles notes that the experiment at Harrogate "should with almost certainty show up a difference of 30 per cent in the two condensates and will give good information about possible differences of 15 per cent" {1102.01, p. 9}.

One of the criticisms of earlier work was that the smoke condensates used were not "fresh"; that is, they had been stored for some time prior to being painted onto the mice. People inhale "fresh" smoke, not old smoke, and any chemical changes that made the stored smoke more toxic to mouse skin might skew the results. So the first experiment conducted at Harrogate was to be a comparison of "fresh" and "stored" condensate.

Besides looking at carcinogenic and cocarcinogenic activity in smoke, Harrogate was also charged with investigating the mechanisms whereby tobacco smoke causes irritation of the respiratory passages. A cocarcinogen is a material that amplifies the action of a carcinogen but is not itself carcinogenic. This research was relevant to the work at Harrogate, rather than simply a matter for competitive improvement of consumer acceptance, for three reasons. Sir Charles notes that irritation could

The term "chronic bronchitis" is a specific diagnosis of some importance. In 1962 British investigators of what we now call chronic obstructive pulmonary disease (COPD) called the disease "chronic bronchitis," while investigators in the United States used the term "emphysema." The term "COPD" was coined to encompass both major phenomena of the condition, the narrowing of airways and the destruction of lung tissue, so that the literature would be easier to follow. Nearly all COPD seen in the United States is caused by cigarettes (7).

At Harrogate researchers would be able to conduct two kinds of tests: (1) by looking at the proliferation of mucus-secreting goblet cells in the lung (a response to irritation), they could determine the potential of smoke to produce bronchitis; (2) by looking for hyperplasia of the epithelial cells lining the bronchi, they could determine the presence of carcinogenesis

and cocarcinogenesis (the stimulation of these cells to divide is an early action of carcinogens). Harrogate was to have the capability to set up both of these experimental models and then to test specific smoke constituents in these systems.

Sir Charles emphasizes the importance of the studies on irritation with the following comments:

I regard the attempt to probe more deeply into the cause of irritation as equally fundamental [to investigating the cancer problem]. Some smoke is irritating, smoker's cough is a reality, and it cannot be good for health to cause this irritation whether or not this irritation has any effect on the incidence of lung cancer . Some of you may regard irritation as so important that you are willing to make a guess and attribute it with but little evidence to a class of compounds such as aldehydes, or you may be ready to take a short cut and attempt to identify irritation by an organoleptic technique [subjective report of people exposed to potentially irritating materials]. This is a matter on which I hope you will express your views. Personally I think the TMSC policy is right; this subject of irritation is just too important to incur the danger of reaching a wrong conclusion due to a faulty technique. Once we have solved the problem of establishing a quantitative test[,] progress in identifying irritating components will be rapid. Whether their removal will be easy is another question, but to identify them will be a good first step [emphasis added]. {1102.01, p. 22}

Sir Charles also describes other work supported by TMSC outside the Harrogate facility: an examination of the relative carcinogenicity of smoke from tobacco that has been cured in different ways; a large, prospective epidemiological study on susceptibility factors (other than smoking) for cardiac and pulmonary disease among 200,000 men; a study of the carcinogenicity of aliphatic lactones (material found in plants that was thought likely to occur in cigarette smoke); an epidemiological study of lung cancer in South Africa and Australia; and the psychological work of Dr. Hans Eysenck. (Dr. Eysenck later received support through the special projects of the Council for Tobacco Research; see chapter 8.) TMSC also funded work on viruses and immunogens as causes of cancer and on the effects of tumor transplants treated in various ways in experimental animals. Taken as a whole, this work plan has a defensive tone: most of these projects sought explanations for the diseases at issue other than that they are caused by cigarettes.

After describing the overall research activities sponsored by TMSC, Sir Charles returns to the experiment on fresh versus old condensate.

[If] fresh condensate has a smaller biological effect than old condensate we do not of course at one stroke destroy the emotional conclusion [that smok-

ing causes cancer]—in fact it remains unaltered—but we do clear the decks of a great deal of previous experimentation and smoke condensate will then be accepted as such a weak carcinogenic agent that other explanations of the association of smoking and lung cancer assume greater importance. Conversely, and this is always a possibility, the biological effect may increase as the condensate is used fresher and fresher. This possibility need not dismay us, indeed it would mean that there really was a chemical culprit somewhere in smoke, and one, moreover, that underwent a reaction fairly quickly to something else. I feel confident that in this case we could identify this group of substances, and it would be worth almost any effort, by preliminary treatment, additives, or filtration, to get rid of it. We should have brought the problem out into the open where it could be attacked. I feel sure you will give your full support to this experiment [emphasis added]. {1102.01, p. 21}

Sir Charles's willingness to accept the possibility that something intrinsic to cigarette smoking could cause cancer—and that, once identified, this "group of substances" could be removed—reflects a greater level of scientific openness than the tobacco industry has evidenced in recent years.

Ultimately, the experiment showed that "fresh" condensate (twenty-four hours old) actually had more carcinogenic activity than "old" condensate (one week old) (see below) {1105.01}.