The Cigarette Papers "d0e5315"

Project Rio

A review of BAT's biological testing program was held at Southampton in May 1983 {1164.26}. The notes on this meeting contain the first reference in the documents to Project Rio, a project designed to organize the company's research on cigarettes having reduced biological activity. Additional information about Project Rio is found in the report of the Rio de Janeiro research conference held in August 1983 {1180.07}. (Chapter 7 discusses the concern that B&W lawyers had about the possible discovery of Project Rio by lawyers for plaintiffs in products liability lawsuits.)

Three distinct components were recognized in Project Rio:

(a)	Phase I would be the design of low activity cigarettes in the 5–10 mg [tar] range, using existing technology and tests.
(b)	Phase II would be the further investigation of such cigarettes with additional tests, possibly after their introduction onto the market. Within the

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	additional tests it is likely that there would be a requirement for a long-term study: Dr. F. J. C. Roe recommended that an inhalation study would be preferable, providing a viable test procedure was available.
(c)	A further stage in the development of low activity products could be envisaged, involving more speculative procedures such as the adventitious addition of materials to cigarettes. However, the work associated with the development and evaluation of such cigarettes would be substantial and might pose problems similar to those faced by the pharmaceutical industry [emphasis added]. {1164.26, p. 1}

The work was to be done through the laboratories in Hamburg, Montreal, and Southampton. The first two parts of the project sound very similar to the things that the R&D group had been involved with over the past generation. The third, though, was something of a departure: the use of additives to reduce biological activity. The document mentions one such possibility: Vitamin A.

The current status of Vitamin A as an anti-cancer agent should be reviewed in the context of the possible addition of Vitamin A (or some derivative) to tobacco. {1164.26, p. 2}

Such a proposal would make sense only if one believed that tobacco causes cancer. Compounds related to Vitamin A found in food had been related to reduced cancer risk, and this information was coming to public attention around this time. However, the use of such cancer-reducing materials as additives "might pose problems similar to those faced by the pharmaceutical industry" {1164.26, p. 1}. The reference here appears to be to FDA regulation.

Toward the end of the 1980s, a B&W marketing executive, Douglas Keeney, left the company to start a new company, CA Blockers. CA Blockers was set up to market a cigarette that used an additive, N-Bloctin, which promised to reduce the consumer's exposure to nitrosamines. The product, Spectra, was regulated as a drug by the FDA because of the implied health claim (2). The FDA regarded N-Bloctin as a drug, since it was intended to reduce the absorption of carcinogens from tobacco smoke, and the agency declared that any product containing N-Bloctin was also a drug. Therefore, it exerted jurisdiction.

By August 1983 the R&D scientists at BAT had decided against actively pursuing Vitamin A as an additive. The decision was based on the results of a literature review, which led to the conclusion "that Vitamin A (and closely related compounds) does not present an opportunity for the cigarette industry directly to influence human response to smoke" {1180.07, p. 4}

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A fear expressed during the discussions about Project Rio in the initial 1983 concept paper was that competitors might publish a ranking of cigarette brands according to the results of mutagenicity tests such as the Ames test. (The Ames test uses bacteria that because of a defective gene are unable to make a particular nutrient that is lacking in a specially prepared growth medium. A mutation at this gene locus can permit the bacteria to grow in the deficient medium. The relative mutagenicity of a test material—such as cigarette tar—can be estimated by the rate at which the material induces mutations that permit the bacteria to grow.)

The possibility of competitors producing a biological ranking of brands e.g. based on Ames test data is real and we should be in a position to respond to such a situation. {1164.26, p. 2}

It is interesting that this threat was seen as coming from other tobacco companies and not from a source such as the Reader's Digest , which had previously caused such problems with its publication of tar and nicotine yields. Clearly, in a country such as the United States, the only competing company that would publish such a list would be one whose product had the least Ames mutagenic activity. In other words, the competitor would have to be a start-up company such as CA Blockers. Nonetheless, the concern that someone else might develop a brand-specific table of mutagenic activity led to a plan to evaluate the Ames test mutagenicity of company brands and those of competitors in selected countries from around the world {1180.07, pp. 3–4}. This work would actually have enabled BAT to publish a biological index table. The work was to be completed on this initial testing by mid-1984.

Project Rio was to be the company's major biological research activity for the 1984–86 period {1180.07, p. 18}. While the work would concentrate on the Ames test, the minutes reflect an attitude of caution about "over-dependence" on this single measure; "more direct tests" were preferred if possible.

Preliminary results from Project Rio are summarized in the minutes of the biological conference held at Southampton in April 1984 {1181.06}.

The Ames is the main screening assay and from the results to date it is clear that:

(i)	Cigarettebrandscan be readily distinguished. This is in contrast with the earlier mouse skin painting results. An unfortunate side-effect is that the sensitivity increases the probability of an Ames League Table

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	appearing. A further unfortunate examination is that, to date, it is not uncommon for BAT brands to have a higher result than those from the opposition.
(ii)	Important fractionation work in Montreal indicates that the Ames activity is associated with the basic materials in cigarette condensate. Again, this is in contrast to the mouse skin painting results, where the bulk of the activity resides in the neutral fraction. Any response to this observation must wait until the initial work in Montreal has been completed.
(iii)	Initial results indicate that reduction in circumference [of the cigarette] reduces activity.
(iv)	Early results from Hamburg indicate that the addition of casings and flavours can increase the Ames activity. Observations from Montreal suggest that certain other casings bring about a reduction in Ames activity.
(v)	Ventilation brings about an increase in mutagenicity which with Canadian cigarettes was not significant. German cigarettes however showed a significant increase. It could be important to evaluate changes in design features with a number of cigarette types as the interaction with the tobacco blend could well be important.
(vi)	Montreal is to produce a review examining variations in design parameters and mutagenicity.

Clearly we need tests in addition to the Ames test and Southampton is obtaining encouraging results with an enzyme induction assay. There was general agreement that the work should be actively pursued. Similarly it was agreed that the "yeast system" showed promise as a useful assay and should be followed up.

The eventual need for a long-term bioassay, preferably based on inhalation, was considered. The significance of such a test to the tobacco industry was discussed, particularly if the animals used were pre-treated with a known initiator such as radon. No firm conclusions were reached but it was agreed that Southampton should explore the feasibility of a long-term assay [italic emphasis added]. {1181.06, pp. 1–2}

BAT scientists had been able to stratify cigarette brands according to Ames activity, but not with mouse skin painting. The constituents of cigarette smoke responsible for the Ames test activity seemed to be different from those associated most strongly with carcinogenesis in the mouse skin–painting model. This result suggests that these were additional constituents of tobacco smoke with negative health effects.

A joint R&D/marketing conference held in Montreal in July 1984 included a report on Project Rio from the Montreal lab {1226.01, p. 85}. The report presents data showing that changes in smoker behavior (compensation effects) could alter Ames test results.

Traditionally, mouse skin painting has been used as an indicator of biological activity. Recently, short term tests such as the Ames mutagenicity test have

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also been used to determine biological activity. With the increase [sic ] use of short term tests, there has been, within the BAT group, discussions focussing on the possibility of legislative bodies using the Ames or other short term tests to assess the "tar quality" or arriving at biological league tables. Project RIO is an example of BAT's response to a potential need for a reduced biologically active product.

...

In all cases, the biological activity of the human generated smoke condensate was compared to standard machine smoking condensate.

...

These results appear to indicate the following:

1)	that human smoking does influence biological activity relative to standard conditions.
2)	certain aspects of human smoking behaviour affect the biological activity of the smoke condensate more than others.

Further studies will revisit this area and investigate in more detail:

1)	those aspects of human smoking behaviour that appear to be most influential with regards to biological activity.
2)	whether these aspects can be modified through product design. {1226.01, pp. 85–86}

The study compared human and machine smoking of two Imperial Tobacco Ltd (Canada) brands, Matinée Extra Mild and duMaurier Light King Size. Matinée had a greater level of "specific biologic activity under human smoking conditions"; that is, Matinée smoke had a higher level of activity per microgram of smoke. In contast, deMaurier had a higher level of activity than Matinée when the data were examined on a "total" (per cigarette) basis. Human smoking profiles had greater "specific" and "total" biological activity associated with them than did the machine standard {1126.01, from overheads used in the presentation}. These data seemed to confirm the study hypothesis that human smoking behavior differs from machine-based smoking enough to be of practical importance.

All in all, Project Rio seemed to leave unresolved problems that had plagued the search for a safe cigarette from the beginning. The Ames test offered a credible short-term assay, but it measured different things from the mouse skin test that had been the standard for decades. The focus at this late stage, three decades on, was still on developing a good assay, when the technological difficulties involved in reducing toxins to safe levels while still delivering a satisfying smoke remained formidable. The whole matter was further complicated by the fact that people do not smoke like machines.

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The bleak prospects for making meaningful progress on this front are reflected in the five themes for R&D found in the minutes of a Group R&D meeting at Wallingford, England, in September 1985 {1182.01}.

i.	Product/smoke quality to be as good as, and preferably better than, competitors.
ii.	Develop technology to be the lowest cost producer and others necessarily of a longer term nature.
iii.	Produce a recognised step forward on the S&H [smoking and health] issue.
iv.	Remove concern for passive smoking by various initiatives including superior products.
v.	Develop alternative products. {1182.01, p. 2}

Progress toward a safe cigarette had become the third objective, was regarded as a long-term objective, and had been diluted to the point that a reasonable goal was seen as merely offering management a "recognised step" in this direction.