Tobacco Documents Online

The case of passive smoking Prof. P.N. Lee N ~

Environmental Tobacco Smoke and'Lung Cancer Approaches to risk assessment P.N.LEE, Ml.A. (Oxon) Independent Consultant in Statistics and Epidemiology 17 Cedar Road Sutton, Surrey, SM2'5DA England . .. ^;. Abstract Based on epidemiological data relating marriage to a smoker to risk of lung cancer, the US Environmental Protection Agency recently concluded that ETS exposure results in approximately 3,000 lung cancer deaths annually among US nonsmokers. Such an estimate is over two orders of magnitude greater than estimates derived by linear extrapolation from data on lung cancer risk in smokers, and relative particulate matter exposure in smokers and nonsmokers. This disparity does not undermine linear extrapolation as a technique, though there must be doubts both about its appropriateness and its accuracy. The disparity reflects more the unscientific nature of the EPA's estimate and their misinterpretation of the epidemiological reports relating lung cancer risk to ETS exposure. When one takes into account the lack of relationship of lung cancer risk in never smokers to workplace or to chil'~dhood ETS exposure, the inconsistency of the evidence on histological type of lung cancer, the serious weaknesses in design evident in~ some studies, and the possibilities of bias due to confounding by other risk factors,

-2- misclassification of active smoking status, misdiagnosis of lung cancer, and the failure to publish negative studies, it is clear that ETS exposure has not been shown to cause lung cancer.

-3- - 1_ Introduction~ - Since the publication in 1981 of reports from Japan [1]i and Greece [2] of an increased risk of lung cancer in lifelong nonsmokers associated with to marriage to a smoker, there has been increasing concern that exposure to environmental tobacco smoke (ETS) may cause lung cancer. A number of authorities [3-8], have concluded that it does, the most recent, by the US Environmental Protection Agency (EPA) estimating ETS is "responsible for approximately 3',000 lung cancer deaths annually in U.S. nonsmokers". In this paper I discuss various approaches to the risk assessment of ETS and demonstrate that differing and plausible assumptions can result in such great variation in the estimated:number of deaths that EPA's figure of 3,060 (2,000' in never smokers and'1,060 in former smokers) has no valid scientific basis. Indeed I show that there is actuall!y no certainty that Lny lung cancer deaths arise as a result of ETS exposure. There are, at least, four basic methods by which~one might attempt to carry out risk assessment of ETS. Cigarette equivalent approach. In this approach, considered in section 2, risk of lung cancer in active smokers is assumed to be adequately quantified by epidemioliogical studies, and risk of lung cancer in relation to ETS exposure is estimated by extrapolation, O based on the equivalent number of cigarettes to which nonsmokers are ~' x os d p . e e w ®

-4- Dose of carcinogen approach. Cigarette smoke contains more than 3,800 constituents, over 40, of which have been classified by the IARC as showing sufficient evidence of carcinogenicity, in some cases only in, animals (5)1. In theory one might use data on exposure levels to each carcinogen to estimate risk in humans. This approach has never been used for three reasons. Firstly, for many carcinogens, the chemical data relate only to mainstream smoke (MS) and one is not able to, quantify levels resulting from typical ETS exposure. Secondly, the observed increased risk of lung cancer in smokers has never been satisfactorily explained by the presence of known amounts of carcinogens in MS, which gives little reasonifor hope that this approach could adequately quantify risk of lung cancer in relation to ETS exposure. Thirdly, it fails to take into account the possibility of interactions between different chemicals, both synergistic an&antagonistic. Animal extrapolation approach. Were there good toxicological d'ata demonstrating that exposure of animals to ETS by inhalation, resulted in an increased risk of lung cancer then one could use standard approaches to estimate risk to humans. However, such data do not exist, so this approach cannot be pursued. Epidemiological approach. The final approach, considered in section 3, is to apply available epidemiological data relating lung cancer risk to ETS exposure to a defined population,. It is this approach that was used by the EPA to estimate their figure of 3,060 lung cancer deaths per year in the US.

-S- 2. Cigarette equivalient aFuroach, Before attempting to quantify the extent of risk of lung cancer from ETS by a cigarette equivalent approach, it is important first to consider whether such, an approach can actually conclusively demonstrate the existence of anv risk. In section 4,of their report the EPA [8] conclude that ETS can be categorizedi as a: group A (human) carcinogen even in the absence of direct epi~demiological data on ETS. They concluded that the epidemiological evidence on active smoking and' lung cancer„ with no evidence of a threshold level of exposure, the "qualitatively similar" nature of the composition of mainstream smoke and ETS, and the evidence of detectable uptake of tobacco smoke constituents in nonsmokers, taken together, are sufficient for ETS to be classified as group A. In considering this conclusion a number of points should be made: were true, it could have been made many years ago. In 1979, for example, there was already extensive evidence available on~active cigarette smoking and it was clear that nonsmokers had some exposure to tobacco smoke constituents, even if at a much lower level than smokers. And yet, the US Surgeon-General, in a 41 page chapter on "Involuntary smoking" in an extensive report on Smoking and Health [9], gave no consideration at all to the possibility that ETS might cause lung cancer. (ii)~ Other reports [e.g. LO]I which~considered that ETS exposure did cause lung cancer, based their conclusion mainly on the epidemiological evidence on ETS an& lung cancer, and merely 4. used evidence of the type considered~by EPA in their section

-6- to support their argument. Put the other way round, the evidence in section 4 is normally considered by the authorities as indicating an effect is plausible, not that it definitely exists. (iii) It is true that the epidemiological evidence on active does not demonstrate the smoking existence of a threshold dose. Typically [9J, the major studies report an increased ri~sk in the lowest grouping of cigarettes/day smoked, which iss certainly statistically significant when the data are considered as a whole. However„ the lowest grouping usually has a consumption of 1-S or 5-10 cigarettes per day,, and the evidence neither establishes nor excludes the existence of a threshold at much lower levels of exposure. There is no goo& evidence that one cigarette a.day increases risk, let alone that 0.1, 0.01 or 0.001 cigarettes a day does. (iv) Epidemiologists often state that there is no safe dose of a carcinogen, a view contrary to the views of many toxicologists, brought up on the views of Paracelsus. Others at this conference will distinguish between, situations in which thresholds are or are not likely to apply. I will merely observe three points. Firstly, one needs to know the mechanism involve6before one can predict whether a threshold is likely to exist or not and in the case of tobacco-associated lung cancer we do not know the mechanism. Secondly, it cannot be assumed that the presence of known mutagens (genotoxins) in ETS points to there being no threshold in relation to cancer risk. This is clear in relation to formaldehyde, which is

-7- mutagenic, but causes nasal cancer by a non-genotoxic mechanism with a very clear threshold [11]. Thirdly, it was clear that the US Surgeon-General did not accept the "no-threshold", "one molecule causes cancer" theory, from~ statements in his 1979 report [9'], viz. "The effect of chronic exposure to very low levels of this carcinogen (benzo[a]pyrene) has not been established" and "It is also not established that nitrosamines can act as carcinogens at these levels delivered by inhalation"'. (v), There are a number of major differences between active smoking and exposure to ETS [12]. In contrast to smokers, ETS exposed nonsmokers breathe in aged tobacco smoke. In vitro tests suggest that aged ETS is less cytotoxic than freshiMS, as inhaled'by the smoker. ETS particles are of smaller mean size (0.1-0.2 µg) than MS particles (0.2-0.4 µg),, and differences in inhalation patterns between smokers and'nonsmokers lead to a much lower rate of particle deposition in the lungs in the case of ETS exposure (11%) as compared to that for smokers (50-90%). Also, the intact clearing mechanism of the respiratory tract of nonsmokers removes particles more effectively than does that of smokers, which may be damaged by smoking. Taking all these points into account, it is clear that one must have strong reservations about the validity of the EPA's argument in chapter 4. Indeed it is interesting to note that Dr Morton Lippmann, the Chairman of the EPA's own Scientific Advisory Board, made it

-8- clear at the open meeting in Washington discussing the final draft, that the argument was not a valid one and should not be used. It is surely a matter of serious concern that the EPA chose to ignore the views of its own scientific advisers. It is clear that any attempt at risk estimation using,the cigarette equivalent approach must be speculative, and subject to a number of unverifiable assumptions. However, although this is probably true for most, if not all', risk assessments, it is still of interest to see what risk this approach produces. Apart from the problems cited above, there are two particular difficulties in conducting the risk estimation. The first lies in the form of dose response relationship to assume, even assuming there is no threshold dose. S'ome of the epidemiological' data on active smoking and lung cancer suggests a reasonable fit to a linear relationship between risk and number of cigarettes per day [9]. However others [13] have suggested that inclusion of a quadratic termi provides a better fit, rendering linear extrapolation likely to somewhat overestimate risk at lower doses. On the other side of the coin, exposure to ETS may have occurred since birth, whereas the smoking habit is not normally taken up until age 15 or so. Although there is evidence [14] that prolonging the period of exposure to ETS has little effect on the risk, ignoring duration might lead to some underestimation~of risk. Taking these counterbalancing points in combination suggests that linear extrapolation might not be an inappropriate procedure., Repace [15] has suggeste& a

a: marker of relative tobacco smoke exposure. In a large study I conducted in 1985 in the UK (18), I found that the corresponding ratios were about 10 times higher, 0.27% in males and 0.13% infemales. Had cotinine been used as the index of exposure in Arundel et al's calculations, this suggests that about 160 lung cancer deaths would have been predicted, still a full order of magnitude lower than the EPA estimates. It is doubtful, however, that estimates base& on cotinine are valid. In the first place, nicotine itself is not deemed to be a carcinogen. Secondly, even if cotinine is used only as an index of smoke uptake, it suffers from the majior problem that while cotinine is a marker of the lung's particulate exposure in active smokers, it is a marker of ETS gas phase exposure in nonsmokers. Comparison of cotinine levels in body fluids of smokers and nonsmokers is therefore misleading.