Tobacco Documents Online

-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