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-I- Environmental Tobacco Smoke and Lung Cancer hpproaches to risk, assessment F.N.LEE, H,A. (Oxon) Independent Consul~ant in Statistics and Epidemiology 17 Cedar Road Sutton, Surrey, SH2 England Based on epldemiologlcal date relating marriage Co a smoker to risk o£ 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, exposure in smokers and nonsmokers. linear extrapolation as a technique, and relative particulate matter This disparity does not undermine 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 ep~demiological 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 childhood 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, 0 0 ~0 0 "-4 0 BATCo document for Mayo Clinic 27 March 2002

-2- ~isclass~ca~ion o~ ac~ s~o~ng s~atus, m~sd~a~nosis of lun~ cancer, and the failure co publish negative studies, iC is clear chat ETS exposure has noc been shown to cause lun~ cancer. BATCo document for Mayo Clinic 27 March 2002

-3- Since the publication in 1981 of reports from Japan ill and Greece [2] of an increased risk of lung cancer in lifelong nonsmokers assoclaced 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 i~ 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 result in such great variation in that EPA's figure of 3,060 (2,000 and plausible assumptions can the estimated number of deaths in never smokers and 1.060 in fo~mer smokers) has no valid scientific basis. Indeed I show that there is ac~ually no certainty that an~ lung cancer deaths arise as a result of ETS exposure. There are, at least, four basic methods by which one mlghc attempt to carry out risk assessment of ETS. Cisarette ecu[valent a~oach. In this approach, considered in secClon 2, risk of lung cancer in active smokers is assumed Co be adequately quantiEiedby epidemiological s~ud£es, and risk of lung cancer in relation co ETS exposure is estimated by extrapolation, based on the equivalent number of c~gare=tes to which nonsmokers are exposed. BATCo document for Mayo Clinic 27 March 2002

Dose of carcinogen aoDroach. 3,800 constituents, over IARC as sh0wln8 sufficie~t cases only in animals (5). Cigarette smoke contains more than 40 of which have been classified by the evidence of carcinogenicity, in some ~n theory one might use data on exposure levels to each carcinogen to estimate risk in humans. ~h£s approach has nevec been used for three =easons. 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 reason for 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 sy~erglscic and antagonistic. 6oimalextraoolat~on approach. Were there good toxicological data demonstrating chat exposure of animals ~o ETS by inhalation resulted in an increased risk of lung cance~ then one could use standard approaches to estimate risk to humans. However, such data do not exist, so this approach cannot be pursued. ~vldem~olo~ical approach. The final approach, considered in section 3, is to apply available ep£demlologlcal data relating lung cancer r~sk to ETS exposure to a defined popula'tion. 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. 0 0 ~0 BATCo document for Mayo Clinic 27 March 2002

-5- "2. C~a~tte e~ui~a~ent an~roach ~e~ore attemp~£ng to quan~i~y ~he extent o~ risk o£ ~ung cance~ ~rom ETS by a cigarette equivalent approach, £c is important ~irsc Co consider whether such an approach can actually conclusively demonstrate the existence of a~rrisk. In section ~ of their repor~ the EPA [8] conclude that ETS can be categorized as a group A (human) carcinogen even in the absence of direct epidemiological data on ETS. They concluded thac the ep£demiologlcal evidence on active smoking and lung level of exposure, the composl~lon of mainstream cancer, wi=h no evidence of a =hreshold "qualitatively similar" nature of the smoke and ETS, and the evidence of detectable uptake of tobacco smoke consc£tuents in nonsmokers, taken together, are sufflclenC for ETS to be ciasslfied as g~oup A. considering this concl~slon a number of points should be made: (1) If it were true, it could have been made many years ago. 1979, for example, available on active nonsmokers had some there was already extensive evideuce clgareCte smoking and it was clear that exposure to tobacco smoke constituents, even if a= a much lower level than smokers. And yet,. the US Surgeon-General, in a ~l page chapter on "Involuntary smoking" in an extensive report on Smoking and Health [9], gave no consideration a~ all to the posslb£1£ty chat ETS might cause lung cancer. Other reports [e.g. 10] which considered Chat ETS exposure did cause lung cancer, based their conclusion mainly on the epldemiological evidence on ETS and lung cancer, and merely ~sed evidence of ~he type considered by EPA in their section 4 ~O O O O~ BATCo document for Mayo Clinic 27 March 2002

-6- co support their argument. Puc the ocher way round, the evidence in section & is normally considered by the aur/%o~ities as indicating an effect is plausibl~, not that it definitely exists. Ic is true that the epidemiological evidence on active smoking does not demonstrate the existence of a threshold dose. Typically 19], the major studies repor~ an increased risk in the lowest grouping of cigarettes/day smoked, which is certainly sua=istically significant when =he data are considered as a whole. However, the lowest grouping usually (iv) has a consumpt~o~ of 1-5 or 5-I0 cigarettes per day, and the evidence nei=her establishes nor excludes the existence of a threshold a~ much lower levels of exposure. There is no good evidence =ha= one cigarette a day increases risk, let alone that O.1, O.Ol or O.001 cigarettes a day does. Epldemiologis=s often stare that there is no safe dose of a carcinogen, a view contrary co =he views of many toxicologists, ~rought 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 involved 5efore one can predict whether a threshold is likely ~o exis= or not a~d in the case of ~obacco-associated cancer we do not k'now the mechanism. Secondly, it canno~ be assumed that the presence of known mu=agens (genotoxins) in ETS points to there being no ~hreshold in relation co cancer risk. Th~s is clear in relation to formaldehyde, which is O O~ BATCo document for Mayo Clinic 27 March 2002

-7- (v) mutagenic, but causes nasal cancer by a nonogenotoxic mechanism with a very clear threshold [II]. Thirdly, it was clear that the US Surgeon-General did not accept the "no-threshold", "one molecule causes cancer" theory, grom statements in his 1979 report [9], vlz. "The efEect oE chronic exposure to very low levels of this carcinogen (benzo[a]pyrene) has not been established" and "It is also not established that n£trosamlnes can act as carcinogens at these levels delivered by inhalation". There are a number of major differences between active smoking and exposure to ETS [12]. In contras¢ =o smokers, ETS exposed nousmokers breathe in suggest that aged ETS inhaled by the smoker. aged tobacco smoke. In vitro tests is less cytotoxlc than fresh HS, as ETS particles are of smaller mean size (0.l-0.2 pg) than MS particles (0.2-0.4 ~g), 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 ef~ectlvely than does that of smokers, which may be damaged by smoking. Taking all these points into account, it is clear than 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 Lippma~n, the Chairman of th~ EPA's own ScienElfic Advisory Board, made it BATCo document for Mayo Clinic 27 March 2002

-8- clear at the open meetlnE in ~ashington discussing the final draft. that the argument was not a valid one and should noc be used. It £s aural7 a matter of serious concern that the EPA chose to ignore the ~fews of its own scientific advisers. It is clear chat 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 wha~ 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 co assume, even assumln~ there is no threshold dose. Some of the epidemiolo~ical data on active smokin~ and lung cancer suggests a reasonable fit to a linear relationship between risk and number of oiEarettes per day [9]. However others ~13] have suggested that inclusion of a quadratic term provides a hatter 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 rot normally 6aken up until age 15 or so. Although there is evidence [14] that prolonging the period of exposure co ETS has little effect on the risk, ignorin~ duration might lead to some underestimation of risk. Ta~ing these'counterbalancing points in co~binatlon suEgests that linear extrapolation might not be an inappropriat~ procedure. Repace I15] has suggested a O. ~O O --4 BATCo document for Mayo Clinic 27 March 2002

-9- dose-relationship in which risk at low dose levels is much higher than that predic=ed by linear extrapola=ion. However, his model totally failed to fit observed data in the active smoking range and is therefore implausible |16]. The other major problem in risk estimation using the cigarette equivalent approach is to know which tobacco smoke constituent to use when computing the cigarette equivalent for ETS exposure. mumber of authors have made it clear that the dose ratio for active smoking to ETS exposure depends dramatically on the constituent considered. Based on results of experimental studies in which healthy male volunteers were exposed to smoking (20 cigs/day) or to ETS exposure (8 hours/day), Scherer and his colleagues [12~ estimated ratios of uptake doses for smoking as compared with ETS exposure. For particulate phase components, exposure from smoking was much higher than that from ETS, with ratios estimated as 1250-3000 for particles, 70-150 for benzo[a]pyrene, 110-1500 for cadmium, and 2300-4500 for tobacco-specific nitrosamines. For nicotine, particle-bound in MS and a gas-phase constituent in ETS, the ratio was estimated to be 75-90. For gaseous phase componen=s exposure was only slightly gr%ater from smoking than from ETS, ra~ios being estimated as 2.7-4.2 for CO, 4-5 for formaldehyde, 1.5-2.5 for volatile nitrosamines, and 3-5 for benzene. The authors point out that the concentrations of the most frequently used ETS markers that were found in their study, were I0 times higher than those found in everyday environments where real-life exposure to ETS may occur. ~n 0 o o 0 O~ BATCo document for Mayo Clinic 27 March 2002