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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

-IO- rhe rationale behind ~be a~emp~s in many countries to encourage a switch ~rom high-tar to low-tar cigarettes is based on the presumption tha~ ~he tumorigenic effec~ of tobacco smoke is mainly a~ribu~able to the particle phase [5]. It would rherefore seem most appropriate ~o use particulate matter as the constituent ~or estimation of cigarette equivalents. Arundel and his collea~ues [17| carried out a de~ailed estimation of never smoker ~un~ cancer risks from exposure to particulate tobacco smoke. They calculated than, in the US, curren~ smokers have a dai~y retained exposure of 310 mg for men and 249 mg ~or women. In contras¢ the average never smoker was estimated to have a daily retained exposure o£ 0.07 mg for men and 0.03 mE for women, equivalent ~o an average of about 1/200~h of a cigarette per day. They further esulma~ed, based on linear extrapolation from lung cancer risks £n smokers, thac i~ ~he US in 1980 there would be a uoCal of 12 lung cancer deaths among n~ver smokers from exposure Co particulate ETS: 8 in men and ~ in women. This is much lower ~ban ~he EPA estimate of~_Q~ lung cancer deachs amon~ never smokers from ETS, 500 in men and 1,500 £n women. (N.B. Arundel et all [17] did not estimate deaths among former smokers, so comparison wi~h the EPA estimate of 1,060 deaths is not possible.) The above estimates indicate that in males never smokers retain abou~ 0.02~ of the amount of particulate tobacco smoke retained by current smokers. For females ~he figure is 0.01%o A number of researchers have used cotinlne, a major metabolize of nicotine, as BATCo document for Mayo Clinic 27 March 2002

-11- am arker of relative tobacco smoke exposure. In a large s=udy I conducted In 1985 £n the UK (18), I found that the corresponding ranios were about I0 times higher, 0.27% in males and 0.13% in females. Had cotinlne been used as the index of exposure In Arundel e._~tal's ealcula=ions, ~hls suggests that about 160 lung cancer deaths would have been predicted, lower =ban the EPA estimates. estlma=es based on eotinlne are valid. In nicotine itself is not deemed =o be a oarcinogen. still a full order of magnitude I~ is doubtful, however, that the first place, Secondly, even if coClnine is used only as an index of smoke uptake, it suffers from =he major problem that while cotinine is a marker of the lung's parnicula~e exposure in active smokers, £U is a marker Of ETS gas phase exposure in nonsmokers. Comparison of cotinine levels in body fluids of smokers and nonsmokers is therefore misleading. BATCo document for Mayo Clinic 27 March 2002

3o ~p.l.demiolo~ical approach There are by now 33 published epidemiological studies oE lung cancer for ehlch results relating to ETa exposure have been separately presented for lifelong never smokers. I have recently prepared an up-to-date assessment of the data from these s~udies [19], drawing partly on an earlier book [20| in which I examined 28 of =hess studies in detail. The 33 studies I considered included all those 30 conside=ed by EPA, with the addition of recently published scudles by Brownson [21] and Stockwell [22}, and a study by Kabat [23] for which results were only presented at a conference. [~ £s convenient first =o describe how =he EPA conducted their risk assessment to reach their estimate of 3,060 lung cancer deaths attributable ~o ETS. The main steps taken, described in full in sections 5 and 6 of their report, can be summarized as fo~lows: (1) Estimate. for never smoking womdn, the relatlve risk of lung cancer associated with marriage to a smoker (or in some studies with living w~th a smoker) in each study. (2) Adjusu the relative risk estimates downward to account for bias caused by a proporWion of current and former smokers misrepresenting themselves as ne~er smokers, coupled w[~h the tendency for smokers preferentially to marry smokers. (3) Demonstrate, by comb£ni~E adjusted ~ela~ive risk estimates from the relevant studies, that uhere are stauis~£cally s~gnlflcant increases in risk ~ relation to ~arriage to/llvlng with a smoker in the II US studies, in the 5 Japanese studies, in the ~ Hong Kong studies, and in the "2 Greek studies, though nou in BATCo document for Mayo Clinic 27 March 2002

-13- the 4 West European s~udies or in the & Chinese studies, and that the overall evidence indicates an associa~ion. Demonstrate that there is a stronger association of lung cancer risk with marriage ~o a heavy smoker (or with marriage to a smoker for a long time) than with marriage to an average smoker. (5) Consider various potential confounding factors (history of lung (6) (7) disease, family history of lung disease, heat sources £or cooking or heating, cooking with oil, occupation, dietary factors) and couclude that none explains the association between lung cancer and ET$ exposure. Classify studies into four "tiers" by a quality assessment, and show ~ha~ the associations generally remain statistically si~nlflcant if attention is restricted to studies considered to be of a better quality. Use the information in (1) to (6) to determine that there is a causal relationship, i.e. that a hazard has been identified. Use an estimate of Z - 1.75 for the relative eotinine level of never smokers married to a smoker and never smokers married to a nonsmoker ~o adJus~ US relative risk estimates to a non-exposed baseline. Thus, relative to a never smoking woman unexposed ~o ET$ ~he risk of a never smoking woman married to a nonsmoker is 1.34 and ~he risk oE a never smoking woman married to a smoker is 1.59. (N.B. the ratio of risks 1.59/1.3& - 1.19 is the relative risk estimate from the I~ US studies, and ratio of excess risks 0.59/0.3& - I.~5 is the Z-factor assumed). BATCo document for Mayo Clinic 27 March 2002

(9) rake an estimate og 9.26, from the A~erican Cancer Society Cancer ~revention Study, for the risk of current and former smokers relative to never smokers, and convert it to an estimate (of 13.8) relative to never smokers unexposed to ETS. (I0) Use estimates of the total number of lung cancer deaths in US women in 1985, and estimates of the relative frequency of never smokers married to nonsmokers, never smokers married to smokers, and ever smokers, in conjunction with the relative risks of 1.3&, 1.59 and 13.8 to calculate that there are 6,970 lung cancer dsaths among never smokers, of which &70 are from ET$ exposure from the spouse and 1,030 from other, non-spousal, sources of ETa exposure. (il) Assume estimates of the ~ncreased lung cancer risk in never smokers in relation to spousal and non-spousal ETS exposure for women apply equally to men, and calculate that there are 80 deaths from ETS exposure from the spouse and &20 from non-spousal ETS exposure. (12) Assume estimates of the increased lun~ cancer risk in never smokers "in relation to KT$ exposure for women apply to former smokers of both sexes who have ~Iven up five or more years a~o, leading to an estimated, f~rther 160 female and i50 male deaths from spousal ETS exposure and 270 female and aS0 male deaths from non-spousal ETS exposure. (13) Sum the numbers for men (I,130) and women (I,930) for never (2,000) and former (1,060) smokers; or for spousal (860) and non-spousal (2,200) exposure, ¢o give a total of 3,060 deaths due to ETS, rounded to 3,000. BATCo document for Mayo Clinic 27 March 2002

-15- In my recent review of the evidence I concluded that the overall evidence from the 33 studies indicated a statistically significant relationship between lun~ cancer risk in never smoking women and marriage to (or living with) a smoker. Of 33 relative risk estimates, unadjusted for covarlates or misclasslflcation of smoking status, 25 were greater than unity (p<O.Ol) and a "fixed effects" meta-analysls [24] gave an overall relative risk estimate of 1.17 (95% confidence interval (CI) 1.08-1.27). This estimate was only marginally changed (to 1.14, 95% CI 1.05-1.23) if one used. where available, relative risk estimates adjusted for covariates, or if one used "random effects" mete-analysis (to 1.21, 95% GI 1.09-1.36). "Fixed effects" mete-analysis only takes wlthin-study variability into account, but "random effects" meta-analysls also considers between-study variability. An association could also be seen separately in studies in the USA, Europe and Asia, estimates (based on unadjusted relative risks and "fixed effects" meta-analysls) being respectively 1.13 (95% CI 1.00-1.28), 1.&O (95% GI 1.06-1.85), and 1.17 (95% Cl ~.05-1,32). 21 studies provided data on risk in relation to exten~ or duration of smokin~ by the husband (or cohabitant). Comparing risk in the most heavily exposed group with that in the overall exposed group, the former had a higher risk in 16 studies and a lower risk in only 4, a significant (p<O.05) departure from chance expectation. Overall the most heavily exposed group had 1.16 times L~ ~O BATCo document for Mayo Clinic 27 March 2002

-16- the risk o£ the overall exposed group, which suggests ~hat the most heavily exposed group had 1.35 (- 1.16 x 1.17) times the risk of the women not married to a s~oker. So far my conclusions were broadly in llne with those of the EPA summarized in points (3) and (~) above. However further exam£natlon of the data revealed a very large number of flaws in the EPA's argument which totally overturned their conclusions. These flaws are summarized below: ~sllure to consider evaluating whether an vital to eonsLder all Although, published, the spouse, of risk in w~rkplace ..and...childhood.....eXposure. When association with ETS e~posure exists, it is indices of exposure wi~h adequate data. in 1986, when a number of the major reviews [3-5] were there was ~ worthwhile amount of data only on smoking by this is certainly not true now. There are I~ estimates never smokers in relation to workplace ETS exposure, which, when combined, provide no evidence at all o£ an association with .lung cancer (RR -- 1.02, 95t CI 0.93-1.12). Similarly there are 14 estimates in relation to childhood ETS exposure from the parents, and again there is no evidence of an association (ER - 0.9&, 95% CI 0.84-I.05). There seem ~o be no strong reasons to believe that smoking by the spouse is a much better marker of ETS exposure than is smoking in the workplace o~smoklng by the parent in childhood [19]. ~t is therefore grossly biassed to do what the EPA did, namely to conceal from the reader the results for these two BATCo document for Mayo Clinic 27 March 2002

alternative indices which show no association at all with lung cancer, and to concentrate solely on the single index, marriage to a smoker, which does sho~ an association. F~ure to consider histoloKig¢l type of. lun~ .. cancer. The association of lung cancer with active smoking is much stronger for squamous cell cancer than for adenocarcinoma. If, as E~A assume, ETS is merely a reduced dose of active smoking, one would expect to see effects, if any, for squamous-cell cancer. In fact the evidence regarding histological type of lung cancer is conflicting. There are four studies where the data on spousal smoking seem more consistent with a relationship with squamous (or small cell) carcinoma, four studies where the data seem more consistent with'a relationship with adeno (or large ceil) carcinoma, one study which found a relationship with both types, and five studies which found no relationship with either t~e. A major weakness of the EPA report is that it makes no attempt co compare and contrast results for the two major t~pes of lung cancer. Consistency is a criterion that EPA cite for testing causality, but which they do not apply in this context. Failure to take i~¢? account properly the posslb~itv of confoundln~. There are three fundamental £1aws in the EPA's argument, First, they only consider confounding relevant if a single risk factor can be shown to explain the whole association between lung cancer and spousal smoking. This is clearly not sensible. More than one risk factor might confound. Second, when ~rylng to determine whecher a factor actually elevates lung cancer risk EP~ BATCo document for Mayo Clinic 27 March 2002

-18- restrlcu attentlen vlrqua~ly completely to evidence from" the ETS/lung cancer studies themselves, ignoring abundant relevant data from other sources. Third,- they ignore the growing evidence |19,25] that ETS exposure is associated with exposure to dietary and other risk factors, and fall to reach the appropriate conclusion that a nonsmoker married to (or living with) a smoker is generally more exposed to other risk factors than is a nonsmoker with no smoker in the household. In a study I conducted recently with my colleagues Allson Thornton and John Fry [25], I identified 33 llfestyle "risk factors", i.e. factors generally perceived to be associated with adverse health consequences, not cancer risk. Of the 33 factors, (p<O.001) Increase~ prevalence in necessarily with increased lung 27 showed a highly significantly smokers of 20+ cigarettes a day compared to never smokers, and only 2 a decreased prevalence. 14 of these factors were also significantly (p<0.Ol) increased in never smokers with a smoker in the household, and non____~ewere significantly decreased. The factors included low fresh fruit and vegetable consumptions high fried food consumption, working in an occupation with a possible cancer risk, low social class, poor eduction, and high alcohol consumption, all factors linked to an increased lung cancer risk. Clearly the question is not whether confounding exists, but what magnitude of bias it causes. Analyses presented elsewhere [19,25] suggest that confounding could explain a material part of the reported association of lung cancer with spousal smoking. It should be noted that the extent to whic~ confounding variables were taken into account in the .epldemiologioal studies of spousal smokln~ on which the EPA's estimate was based was very limited. Thus over 0 C~ BATCo document for Mayo Clinic 27 March 2002

-19- half ?.he studies where spouse smoking was the index of exposure failed to restrict attention to married subjects, thereby producing a serious confoundln~ between potential effects of ET$ exposure and potential effects of Furthermore. although numerous risk factors, marital status (and its correlates). many studies reported having recorded few took any account of these in analysis. Thus, 31 of the 53 studies did not adjust for dietary factors, one of these being a study [22]. which actually reported a striking relationship between diet and lung cancer among never smokers in another paper [26]! Failure to eo~re~C, fully.for bias ~ue tq misclassiflcation of active s~_._~. Adjustment for misclassificatlon is a complex issue involvin~ a n~mber of assumptions that are not easily justified, and variables that are not precisely known. In the EPA report, Wells estimates the bias to be negligible, only increasing the overall relative risk estimate by a factor o£ about 1.02. However, as discussed in detail elsewhere |27], there are two major reasons why this analysis may understate the effect of bias. One reason lles in the error of applying a mlsclasslflcation rate, estimated from data virtually all of which comes from North American, European and Australian populations, to results from lung cancer studies conducted in Asia. The fact £s that in some countries, such as ~apan, smoking by women is considered socially unacceptable. Consequently misclassification rates are- likely to be much higher there. The second reason lies in underestimat£ng the extent of mlsclassification i~ the countries for which data are available. CD ~D BATCo document for Mayo Clinic 27 March 2002

-20- Elsewhere {19] I present the results of analyses adjusting the mete-analysis relative ~isk ~or the US studies for various plausible values of the two key parameters, the mlsclasslfication rate and the concordance ratio (the measure between the smoking habits of regarded as the most plausible of the extent of the association husband and wife). Uslngwhat I estimates (2.5% misclasslfication, concordance ratio of 3.0) reduced an unadjusted relative risk of 1.13 (95% CI 1.00-1.28) to 0.96 (95% CI 0.8~-I.09). Even assuming only a 1.0% miselasslfleatlon rate reduces the =elatlve risk estimate to 1.06 (95% Cl 0.9~-1.20), halving the estimated excess risk and making i= become non-slgnificant. Failure to address public~t~o~ bias. It is well known that any meta-analysis should consider the possibilities of bias due to failure to publish null studies, hut EPA do not consider =hls issue at all. In fact there is some evidence of this, with a tendency for relative risk estimates to de=tease with increasing sample size. Thus, in ~he Ii studies with less than 50 lung cancer cases, the relati~ risk estlma~a was 1.41 (95% Cl 1.02-1.93); in the 12 studies with 50 to I00 cases it was 1.33 (95% Gl 1.12-1.58); and in the 10 studies with more than 100 cases it was i.i0 (95% CI 1.00-1.21). Failure_to. test for @ffects o~studv weaknesses. Meta-analysls is conventionally used to combine results" from similarly designed randomized controlled trials conducted in different populations. It is much more open to question when, as here, it is applied to BATCo document for Mayo Clinic 27 March 2002

, . Hmll I I II non-randomlzed eptdemiological studies o£ varying design. Before acceptin~ an overall estimate in such circkultstances i~ seems prudent to see whether relative risk estimates vary systematically by dlfferen= aspects of study design. The EPA did not conduct such analyses but elsewhere |19] I have done so. One clear conclusion was ~hat studies class~fled as seriously weak on one or more o£ six crilerla (fewer than 1O lung cancer cases, cases and controls from different hogpitals, cases and controls interviewed ~n different places, next-of-kin used co supply data for a much higher proportion of cases ~han controls, controls and cases unmatched on vital stalus, no derails provided at all on the controls) had much higher relative risk estimates than those with no such weaknesses. Indeed the 16 seriously weak s~udles included the 12 studies (of 33) with the hi~hes~ estimates (p<O.O01) on a rank test. My analysis also detected one other factor strongly associated with relative risk, namely year of publ~catlon of the study. Studies publlshed, after 1988 reported no increase in lun~ cancer risk in relation to marrla~e to (or livinK with) a smoker (RR - 1.02, 95% CI 0.gl-l.15), while a higher relative risk was reported in studies puhllshed in 1981-85 (RR - 1.29, 95% C~ 1.09-1.52), or in 1986-88 (KR - i.~, 95% CI I.~0-1.68), Failure to cpn~ider bias., due ~?.i~accuracy. of dlaKnosls, While bias due to selection of indices of exposure showing an association at the expense of those that do noK,. to confounding, to misclasslfica~ion of smoking status, to failure to publish null studies, and ~o poor study design, would tend to result in O ~o O O BATCo document for Mayo Clinic 27 March 2002

-22- overestimation of the r~sk associated with E~S exposure, bias due co mlsclassiflca~ion of diagnosis would underestimation of risk. However, difference in relatlve risk bet~een be expected to result in some since there is no significant the 16 studies where all or virtually all the diagnoses were histologically confirmed (RR - 1.26, 95% Cl 1.10-i.~3) and the 17 studies where this was not the case (RE - 1.11, 95t Cl 1.00-1,2a), this does not seem to be a major factor. Over~nterpretaClon o~ the do~e=r~sponse .da~a, of 16 studies testing for upward ~rend significant (p<O.05) association and tha~ response is very supportive of would be an unlikely result of The EPA noted ~ha= I0 reported a statistically "this evidence of dose a causal relationship because i~ any operative sources of bias or confounding". The EPA's interpretation of ~his is misleading fo~ a number of reasons. Firstly, their trend analyses included the non-exposed group, many studies being cited as having a significan~ trend actually showing little or no ~ariation in risk between the exposed groups. Second, studies that report an association bstween spouse smoking and lung can~er risk are more likely to present dose-response data than those that do not. Third, in some studies authors, faced with a choice of indices of exposure, presenU detailed results for the index showing the strongest dose-~esponsa relationship [28]. Finally, a number o~ the sources of bias, including mlsclassificaClon of active smoking status and confounding by diet, would in fact be expected to produce a spurious dose-response relationship BATCo document for Mayo Clinic 27 March 2002

1~ one takes all the above considerations into account ie is clear that the epldem£ological evidence does not provide convincing support to the no~ion that ETS exposure causes lung cancer. There are a number o£ sources o£ bias ~hich together could easily explain the ohsewed association between lung cancgr and marriage to (or liv£n~ with) a smoker, which is veak and marginally significant. Clearly under these circumstances it is not seustble to attemp~ to estimate deaths occurring annually "as a result of" ZTS exposure. However, some additional comments should be made on certain aspects of ~he EPA's ~Isk estimate. Use of dubious .Z-faeto~esttmates. For a given relative risk estimate in relation to marriage to a smoker, the proportion of deaths attributed to ETS exposure reduces sharply as the estimated value of the Z-factor (the ratio of ETS exposure in never smokers married to a smoker no that in never smokers married to a nonsmoker) increases. ~u the ~986 NRC report (&), a Z-factor of 3.0 was used. Given a relative risk e@tlmate of 1.19, this would imply that 2~% of lung cancer deaths in never smokers married to a smoker are attributable to ETS exposure, "and that i0~ of deaths in those married to a nonsmoker are. For the Z-factor of 1.75 used by EPA, these percentages rise to 37% and 25%. It is in fac~ very doubtful whether I.~5 is an appropriate estimate, for reasons discussed in de~ail by Layard ~29] and Sears 130], who cite data from a number of US studies showing substantially hisher Z-factors, exceedin~ a.O. BATCo document for Mayo Clinic 27 March 2002

Unjustified ez~Tapo~at~o~ to male~, ex-smokers and non~spousa| s~urce~_of ETS.ex~osure. O~ ~he 3,060 lung e~nser deaths attributed by E~A to ~ exposure, only 670 are attr£buced to spousal exposure £n~emales. The remaining deaths attributed are in males, ~n ex-s~oke~s and/or are at~ri~ted to non-spousal exposure, a~ calculated i~direc~lyby extrapolation f~om the spousal results for tamales. And yet ~here are direct epidemiological data ava£Iab~e on risk in males, on risk in ex-smokers, and on risk In relation to other forms of ETS exposure, significantly increased risk. ex-smokers are quite limited, all of which show no statistically While the data in males and in the da~a on workplace exposure is quite substantial, and shows no association with lung cancer risk. I~ is clearly not scientifically sensible to use data on spousal ETS exposure to estimate effects of non-spousal ETS exposure (of which workplace exposure in clearly a major part) indirectly, ignoring the direct evidence. 0@ the e.st.~ated.number of lunz The EPA note [9] that thei~ of approximately 3,000 lung Let us actually consider the Undue confidence in the accuracy cancer.de.~hs.attr£buted to ..ETS. overdll confidence in their estimate cancer deaths is "medium to . high". facts about this estimate: (1) It depends on an estimate of relative risk associated with husband's smokln~, based on iI US s~udies, of I.~9 which has 95% confidence limits as wide ~s 1.04 to 1.35. These confidence limits, which only reflect sampling variation O O O O Co BATCo document for Mayo Clinic 27 March 2002

-25- within the studies, would at once imply that the estlmated number of deaths from spousal smokin~ in females of 470 should have confidence limits at least as widely spread as 99 to 866. The estimate is adjusted for mlsclassifi¢atlon of smcklnE status, but the eonfldence limits do not reflect the considerable uncertainty in the parameters used in the adjustment. As noted above, using alternative, apparently more plausible assumptions, the point estimate of ~70 would reduce markedly, perhaps even to zero. Certainly the confidence limits would ~0 below zero. (Ill) NO adJustmenn is made for other sources of bias, noted above to be relevant, including confounding, publica£ion bias and weaknesses in study design. (iv) The estimate of 470 is contingent on the Z-factor used. Using 3.0 instead of 1.75 would approximately halve a Z-factor of this estimate, 72% of the (v) total of 3,060 deaths is attflbutable to non-spousal ETS exposure, this being calculated by extrapolation from the data for spousal ET$ exposure ignor~n~ the evidence that workplace ETS exposure is not associated with lung cancer risk. (vl) 35% of the total deaths attributed are in ex-smokers, and 37% in males, with actual data available being ignored, and .the assumption that results for females apply to males and that results for never smokers apply .to former smokers being dubious, and adding further uncertainty to the overall estimate of 3,060 deaths. O "-4 CO BATCo document for Mayo Clinic 27 March 2002

-26- o o Clear~y £n no sense estimate of 3.060 deaths, EPA express. can one have any real confidence in the let alone the "medium to high" conEidence BATCo document for Mayo Clinic 27 March 2002

-27- Conc~U~.~cns Assuming that a linear no-threshold mode~ applies, and that particulate matter deposited in the lung is an appropriate index of e~osure, it has been calculated [17], on ~he basis of the lung cancer risk in smokers, and the relative deposition of tobacco smoke-related particulate matter in the lun8 in smokers and nonsmokers, that 12 lun~ cancer deaths occur annually in the US as a result of ETS exposure. This estlma~e is over two orders of magnitude different from the recent EPA estimate of 3,060 deaths, based on epldemiological reports of an increased risk of lung cancer in never smokers married to smokers. Does this imply that the estimate produced by dose extrapolation is seriously incorrect? Cerualnly it is difficult to h~ve any very ~reat confidence in this estimate, because of doubts reEarding validi~y of the linear .o-threshold model, and of the approprla~e index of exposure ~o use for dose-response extrapolation. However, this does non necessarily mean that the estimate is seriously incorrect. ~ha6 is clear is chat the epidemlologlcally based estimate of 3,060 deaths has no sclen~Ific justification whatsoever. Detailed examlna~ion of the evidence reveals that no effec~ of ETS exposure on lung cancer has Seen established at all. ~t is~ of course~ impossible co prove a negative, 5u~ it is'clear that very much lower estimates of deaths, 30, 3 or even 0.3 are totally consisten~ with ~he data available to date. ~t is thus no~ possible to use the ep~dem~olo~ieal data on ETS exposure as a~y sort oE gold standard to validate estimates produced by linear extrapolation from the e?idemio~o~ical data rela~ng ~o active smoking. BATCo document for Mayo Clinic 27 March 2002

-28- References 1. H¢=ayama To Nonsmoking wives of heavy smokers have a higher risk o£ lung cancer: a study from Japan. Br ~ed J 1981;282:183-5. 2. Trichopoulos D, Ka~andidi A, Sparros L, Hac~ahon ~. Lung cancer and passive smoking. ~nt J Cancer 1981;27:1-~. 3. ~a~tonal ~esearch Council. Env£ror~en~al Cobaoco smoke. Heasurtng exposures and assessing health effects. ~ash~ngton, National Academy Press, 1986. 4. US Surgeon-General. The health consequences of involuntary smoking; a report of the Surgeon-General. Rockville, US Depart~en~ of Health and Human Services, Public Health Service, 1986, (CDC)87-8398. 5. ~nternatlonal Agency for Research on Cancer. ~ARC monographs on the evaluation of the carclnogen~c risk of chemicals to htu~ans, vol 38: ~o~acco smoking. Switzerland, ~AEC, 1986. 6. Auscral~an National Hea~h and Medical Eesearch Council. Effects of passive smo~n~ on health. Austral~a, L986. 7. Independen~ Scientific Co~t~ee. Fourth repor~ on smoking and health. London, Her MaJes~y*s S~a~ionery Office, 1988. 8. ~S Env~ro~ental Protection Agency. Respiratory health eff~c~s of passive smok~g: lun~ cancer and o~her disorders. ~ash~ng~on DC, 1992, EPA/600/6-90/O06F. 9, US Surgeon-General. Smoking and health; a report Surgeon-General. ~ash~ns~on, US Department o~ Health, Education and ~elfare, Publlc Health Serv[ce, 1979; (PHS)79-50066. BATCo document for Mayo Clinic 27 March 2002

i0. Wald NJ, Nanchahal K, Thompson SG, Cuckle HS. Does breaching other people's tobacco smoke cause lung cancer? Br Mad J 1986;293:1217-22 ii. Casanova M, Hock H d'A. The impact of DNA-proueln cross-linking suudles on quantitative risk assessments of formaldehyde. CIIT Acu£vities 1991;ii:1-6 12. Scherer G, Conze C, TrlckerA~, Adlkofer F. Uptake of tobacco smoke constituents on exposure to environmental tobacco smoke (ETS). Clin Investig 1992;70:352-67. 13. Doll K, Peto R. Cigarette smoking and bronchial carcinoma: dose and ~ime relationships among regular smokers and lifelong non-smokers. J Epidemlol Community Health 1978;32:303-13. 14. Derby SC, Pik~ MC. Lung cancer and passive smoking: predicted effects from a mathematical modgl for cigarette smoklnE and lung cancer. Br J Cancer 1988;58:825-31. ..15. Lee PN. An estimate of adult mortality in ~he United States from passive smoking. Further comment. Environ Int 1992;18:315-7. 16. Repace JL, Lowrey AH. estimating mortality 1991;17:386-7. Observational vs extrapolative models in from passive smoking. Environ In= 17, Arundel A, Sterling T, WelnkamJ. Never smoker lung cancer risks from exposure to particulate tobacco smoke. Environ Int 1987;13:409-26. 18. Lee PN. Passive Smoking and Lung Cancer. Association a Result of Bias? Human Toxicol 1987;6:517-24~ O~ BATCo document for Mayo Clinic 27 March 2002

-30- 19. Lee PN. An assessment of the epldemiological evidence relating hung cancer risk in never smokers to environmental tobacco s~oke e~posure. In: "Environmental Tobacco Smoke". Ed: H Kasuga. Sprlnger-~erlag, New York 1995. 20. Lee PN. Environmental tobacco smoke and mortality. Karger, Basle, 1992. 21. Browns0n RC, AlavanJa HCR, Hock ET Loy T$. Passive smoking and nonsmoklng women. Am 3 Public Health 1992; lung cancer in 82:1525-30. 22. Stockwell HG, Goldman AL, Lyman CH, Nass CI, Armstrong Plnkham PA, Candelora EC, Brusa MR. Envlronmental tobacco smoke and lung cancer in nonsmoking women. J Nail Canoer Inst 1992;8~:1417-22. 23. Kaba~ GC. Epldemlologlc studies of the relationship between passive smoking and lung cancer. Washington, 1990 Winter Toxicology Forum, 1990:187-99. 2~. Fleiss JL, Gross A~. Meta-analysis in epidemiology, with special reference to studies of the association between exposure to environmental tobacco smoke and lung cancer: a critique. $ Clin Epidemiol 1991;4&:127-39. 25. Thornton A, Lee PN, Fry JS. Differences between smokers, ex-smokers, passive smokers and nonsmokers. Submitted to Journal of Epidemiology and Community Health 1993. 26. Candelora EC, Stockwell HG, Armstrong KW, Pinkham PA. Dietary intake and risk of lung cancer in women who never smoked. Nutr Cancer 1992;17:263-70. BATCo document for Mayo Clinic 27 March 2002

-31- 27. Lee PN. An estimate of adult mortality in ~he United States Erom passiv8 smoking. Environ ~nn 1993:19:9~-I00. 28.'Lee PN. Lung cancer in nonsmoking women: a multlcenter case-control study. Cancer Epldemlology. Biomarkers and Prevention 1992;1:332-3. 29. LayardMg. The background ad~us~menu In risk assessmen~ oE environmental ~obacco smoke and lung cancer. Environ Int 1992;18:453-61. 30. Sears SB. Presentation before the EPA°s Science Adv£sory B~ard. ~ashlnguon DC, July 21-22, 1992. BATCo document for Mayo Clinic 27 March 2002

THE INTERNA~ONAL CENTER FOR A SCIENTIFIC ECOLOGY The Center has been created at the beginning of 1993 under the French law for nomprolit organizations. The purpose is to answer the request from a number of the Heidelberg Appeal signatories in view to extend its impa~t in examining actual issues the ~ientific community is confronted with. The purpose of the Center is expressed in the by-laws : "The purpose of the Assodarion is to promote and fadlitate exchange of scientific knowledge, based on sdentit'~ data. regarding the protection of mankind, other living species, natural sites and the resources ot" the planet. The Association thus proposes to provide the most relevant scientiF~: facts to the authorities responsible for developing environmental protection policies, to the Society which, under the principle of transparency, is called upon to express its point or view. as well as to all sodo.economital partners who want to contribute in both the conservation of the Earth and the Iong-term development of its populations." The Board of the Center includes in particular: - Mr Pierre Joly. President of the ~.ssociation Fran(aise pour la Recherche Th~rapeutique : former President of the International Federation of Pharmaceutical Manufacturers Association ; - Mr Constant Burg. honorary membei of the State Council ; honorary managing director of INSERM : President of the lnstitut Cude: - Mr Gilbert Rutman. chief mining engineer: President of the Conseil Natioflal des Ingdnieurs et des Scientifiques de France: - i~rof. $. Fred Singer. Doctor of Physical Science : President of the Science & Environmental Policy ProJect : former Director US Weather Satellite Program : Dean of the School of Environmental Sciences. University of Miami : Deputy Assistant Administrator of US Environmental Protection Agency (EPA) : - Mr Gary Nash. Secretary General of the Interhational Council on Metals and the Environment ([CME) : former Director General in the Canada Department of Energy. Mines und Resources : • Dr. Michel Salomon, coordinator of the Heidelberg Appeal ; former science journalist : magazine editor. International Center for a Scientific Ecology Centre International pour une Ecologie Scientifique Is the concept of linear relationship between dose and effect still a .valid model for assessing risk related to low doses of carcinogens ? An international scientific seminar organized by the International Center for a Scientific Ecology May 10, 1993 - Paris (P~. nce) (Hilton Hotel. 18. Avenue de Suffren o 7~015 Paris) Under the patronage of the following Associations • The Science and Environmental Policy • Entrepdses pour rEnvtronnement • Consell National des Ing~nleurs et Sclentlflques de France l~e Seminar devoted to the linear dose/response relationship Is the first event Inffiated by the Internationa| Center for a Scientific Ecology. International Center for a SdentJflc Ecology 10. avenue de Messine. 750~8 Paris. France Phone : 33 1 45 62 20 03. Fax : 33 1 42 89 O0 59 0 0 BATCo document for Mayo Clinic 27 March 2002

Mot~day May 10.1993 8/8.15 aJ~ 8.15/830 &m. 8.3019 a.m. 91920 a.m. 9.2019A0 a.m. 9A0/10.00 10.00/1020 IO.ZO/1030 lO.30/Noon AGENDA • Reglst~Jon - Coffee. • Welcome address by Pierre Joly, Chairman of the International Center for a ScientiF¢ • Opening speech by the ChaTmlan of the Seminar, Prof. Bruce IL Ames (B/oto9/st, D/r. NaE Inst. of Environmental Heal~ Sdences Center. BenV.ete2. • How ~ologlcat|y based mode~s m~ hetp extrapolating cancer risk to low doses. Prof. (~qxg L~ebed¢ (Fred Hut~hfn~o~ Cancer ReseaKh Cent~. Seattle. U.S.A). • Critical approach of mathematl(:al extrapolation. Prof. EUe~ne (Tmicologls~. Hopital Femand-Wldal, Paris, • Do mden~ studies p~dict human cance~ ?Pmf. Aaron Wildavsk;y (Unkc, rsity of Califom~ Berkeley, IIS.A). • ~he Delaney amendmenl: ar~ its consequences on the American Rgulatton. Prof. Fred S, ~nger (Physick~ forme~ Oic US Weather Satellite Program ; P~sident Science 8~ Env/ronrnenta! Foilcy Project, USA.). • Coffee break. • Case studies: Predictions and reali~o - The Arsenic case. Prof. Gerhard St~hre¢ (fom~r chief Dept. of chemical dsk~ Resea~n Inst. Sloan-Ke~tering. IIS~ ), - The Asbestos case. Prof. J. Corbett M¢Donald (Ep/demlologis¢. Resea~.h Unit in Epld.. Hear~ and Luhg Inst.. London, U,f~). - The case of chlorine and dedvated products (VCM). Dr Wemer Frelesleben (Oir. European Coundl o~ Vin21 Manufacturers, Brussels. Belgium). . The DDT case. Dr W1111am flazelffne (Ph. 0., entornot~glst, former Manage" of mosquito abatement in Callfomla, USA). - The case of radiations. Prof. Bernard L. Cohen (University of PiGsb~irgh ]. Noon/1230 p.m. 17_30/Z 213 p.m. 314_30 p.m. 4.30/5 p.m. 5/6 p.m. End of Seminar. 6,'7 p.m. • Special meeting with International scientific press for Q/A and interviews. Parttdpents to the sdentlflc Panel Invitations have been sent to a number of distinguished intemaLional scientists. We expect twenLy to thirty sdentists to attend. Audience A number o~ personalities from industry and administrations 'will attend the Seminar as observe~ Their flnanolal cofltdbutione ma~dng the meeting possible. Organbatton The Seminar is organtsed by the In~mational Center for a Scientific Ecology (see introduction to the Center In cover page). The sdentiflc work is organLsed by .Dr Michel Salomon. Coordinator of the Heldelbe~J Appeal. "lYanslation Lectures and comments may be either In English or FRnch. Simultaneous translation will be provided in both languages throughout the Seminar. Press Conference International scientificjo~matlsts are asked to reg|ster If they wish to attend the sessions. A press conference will be held by the members of the scientific panel at 6 p.m. on May 10. 1993. C~ 0 BATCo document for Mayo Clinic 27 March 2002

26:0./. "93 17:S3 '~33 1 42 8~ O0 5;] CE$~k"L~OPR-~-T-IS "~'* - [~002 TO HEADS OF STATES AND GOVERN1VIENTS ~cienti~c ~nd in~e~ua~ ceremony. ~he ~ubject m~t~r ra~ed by the He~e~ Appea~ and the fruitful deba~ it h~ engen~red ~re prompt~g the ~nvolvement ~f a number of $~[ent~ts and intellectuals. The vaIu~ embr~ed by ~he Appeal remain a topic of ongoing We wa~t to make our full contribution to the preservation of our common heritage, the Earth. We are however worried, at the dawn of the twenty.f~rst centm7, at the emergence of an irrational ideology which is opposed to scientific and iudustrial progress and, impedes economic and serial development. We contend that a Nataral State, sometimes idealized by movement~ with a tendoncy to look toward the past, does not exist and has probably never existed since man's first appearance in the biosphere, insofar as humanity has always progressed by i~¢reasingly~ harnessing Nature to its needs • a~cl not the reverse. • W e fully subscribe to the objectives of a scientific ecology for a universe whose resom'ces must be tak~ stock of, monilored and preserved. But we here~vith demand that this stock. taking, monitoring and pressrvatlon be founded on scientific criteria and not on irrational pro-conceptions. We stress that m~uy essential humau activities are carrivd out either by manipulating hazardous substances or in their proximity, and that progress and development have always involved increasing control oyez hostile forces, to the ~nsfi~ of mank~d. We thex~f~re ~nsider that s~eR~fi~ is uo more than an extension of this ¢ontinu~ pro~ss toward the improved life of furze generations. We intend to assert science's responsibility and duties toward society as a whole. We do however ~otewarn the authorities in cha~ge of our planet's destiny against derisions which are supported by pseudo- scientific arguments or false and non relevant data. We draw everybody's attention to the absolute necessity of helping po~r countries attain a level of sustainable development which matches that of the zest of the planet, protecting them ~om troubles and dangers stemming from developed nations, and avoiding their entanglement in a web of unrealistic obligations which would compromise both their independence and their dignity. The greatest evils which stalk our Earth v.re ignorance and oppression, and not Science, Technology and Industry whose instruments, when adequately man~ed, are indispensable tools of a ~t~xe sheped by Humanity, b:r itself aud for itseli. overe, omiug major pr ob:.em.~, like overpopulation, starvation :.~md v.':,r~dw~d~ diseases. du~y vign~ avd st~dng )'our academic titlts ~nd far p.'o~s. [~.a~: pm i¢io ~ ~ : Dr ~f. .~alor, lon, coordinator of the Fl~del~¢q~ A~I. ;0. ao~nua de 3f¢~si.na 7~008 Paris, Frar.~e. F~.~: (33:- 1 4'2 89 O0 5,0. ideidelbe~. Aprti 14 (3rd rgt'.icm~) BATCo document for Mayo Clinic 27 March 2002

Is the concept of linear reiationship between dose and effect still a valid model for assessing risk related to low doses of carcinogens ? May 10, 1993- Paris 21 Avd11993 BATCo document for Mayo Clinic 27 March 2002

International Center for a Sdentific Ecology i li'll II Centre International pour une Ecologie Scientifique Is the concept of linear relationship between dose and effect still a valid model for assessing risk related to low doses of carcinogens ? May 10,1993 - Paris • How biologically based models may help extrapolating cancer risk to low doses ................................................................................ Prof. Georg Luebeck • Do rodent studies predict human cancers ? ............................................. Prof. Aaron WildevsW • The Asbestos case ...................................................................................... Prof. J. Corbett McDonald • The case of chlorine and derivated products (VCM) ................................ Or Warner Frelesleben • The DDT case ............................................................................................... Dr William Hazeltlne • The case of radiations ................................................................................ Prof. Bernard I.. Cohen • Endcavouring new shores in the estimation and assessment of the cancer risk by environmental materials (abstract) ............................... Pr Erich Hacker • Exposure-Response: Asbestos and Mesothelloma .................................. Health effects of historical exposures to Asbestos .................................... Prof. Douglas Liddell 21Avd11993 International Center for a Sdentlflc Ecology 10. avenue de Messine. 75008 Pads. France Phone: 33 1 45 62 2003. Fax: 33 1 42890059 BATCo document for Mayo Clinic 27 March 2002