Tobacco Documents Online

. 259 Adult mortality from passive smoking r Table Al. Annual U.S. male lung cancer dcaths from passive smoking. Relative Risk Constant at 2.1 Age of Death Nevcrsmoker Death Rate perr100.000 Nonsmoker Population 1000's Fraction Exposed Exposed Popqlation 1000's Excess Death Rate Deaths 35-39 1.8 5156 0.74 3815 1.09 42 40-44 2.9 4136 0.72 2980 1.78 53 45-49 4.5 3477 0.70 2440 2.80 68 50-54 7.0 3431 0.66 2260 4.46 101 55-59 11 3423 0.63 2155 7.15 154 60-64 16 3489 0.59 2054 10.7 219 65-69 23 3150 0.54 1695 15.9 269 70-74 33 2443 0.45 1099 24.3 267 75-79 49 1712 0.37 633 38.3 242 80-g4 72 921 0.27 249 61.1 152 85+ 95 516 0.08 41 96.0 39 Totals 15.9 31944 0.61 19320 8.26 1606 Appendix A Details of death calculations Tables A1 and A2 show the details of the death calculations for male lung cancer and female cancer other than lung and are similar in all respects to Table 6 in the text except that no declining relative risk calculation is shown for male lung cancer since the evidence that was available (Hirayama, 1984a) indicated no such decline. In Table A3 the details are given for the development of the never smoker relative risks for heart disease that. were used in the death calculations. As noted in the text, the 1963 neversmoker heart death rates by 5-year intervals were ob- tained by dividing the never smoker coronary heart deaths in Hammond's (1966) appendix. Table 14, by the person years in his appendix tables 2a and 2b. Reduction factors to account for the change in heart death rates between 1963 (end of Hammond's study) and 1984 were then developed by 10 year age intervals from the age specific heart death rates in table 24 of Health U.S.1986 (NCHS,1986). These reduction factors were modified for the fractions thought to be due to smoking which were taken from a staff report of the Office of Tech- nology Assessment (OTA. 1985) to yield a combined never smoker reduction fattor, interpolated back to 5-year age in- tervals, for application to the Hammond never smoker death rates. These modified rates, which are for enrollment age and therefore about 2 years younger than age of death. were then plotted against age of death on semi-log graph paper. Trend lines were then drawn through the female and the male points to yield the values in the last column of Table A3. Tables A4 and AS are simply the details of the heart death calculations as in Tables 6. Al, and A2 for cancer. The deaths shown in Table 7 resulting from the corrections for misclassification were calculated from the relative risks in lines 4 of Table 5 taken as constant over the age range. The modification of the observed relative risks for smoker mis- classification as shown in Table 5 are based on misclassified smoker relative risks calculated as follows. Based on as yet unpublished work of Wells on misclassification it was assumed that self-reported current smoker relative risks for male and female lung cancer in the U.S. and U.K. were 11 and 7, and 4.6 and 2.7 lot male and female current smokers in Japan Table A2. Annual U.S. female deaths from cancer other than lung from passive smoking. Exposed Relative Risk Constant at 1.16 Relative Risk Neversmoker Population Declining Age of Death Death Rate per 100.000 (Table 6) 1000's Excess Death Rate Deaths RR Deaths 35-39 28 5781 3.9 225 4.5 1321 40-44 48 4252 6.7 285 2.9 1411 45-49 80 3423 11.2 383 2.0 1449 50-54 125 3355 17.6 589 1.56 1579 55-59 190 3495 26.8 937 1.30 1591 60-64 265 3228 37.7 1219 1.18 1352 65-69 355 2912 51.1 1487 1.12 1144 70-74 470 2030 68.7 ' 1395 1.08 729 Ln 75-79 600 1472 89.0 1310 1.05 431 m 80-84 85+ 750 900 537 100 114.7 141.7 627 142 1.034 1.022 138 W co 20 m i Totals 256 30595 28.1 8599 11165 N m m ~o

• • 260 A. J. Wells • Death rates from Hammond (1966) Age at enrolled age Range per 100600 1984 1984 Neversmoker Decline. Fraction Neversmpker Hammond's heart in heart of decline Death Rate N.S. D.R. death rate DR's Sfc due to as S4 of 1963 corrected by age of 1963-84 smoking (smoothed) for decline death -•Table A3. Development of 1984 neversmoker heart death rates versus age. Feinales: 35-39 7.1 49 3.5 2.0 .i8 0 40-44 14.1 55 , 7.7 4.4 45-49 20 4 60 ' 2 12 2 10 . 37 0 . . 50-54 45.5 63 ' 28.7 23 55-59 104 36 0 64 66 51 60-64 243 64 156 113 . a 65-69 475 . 64 304 24Q G 70-74 961 37 0 . 64 .. . 615'. . 480 . 75-79 1648 63 1072 870 35 0 80-84 2774 70 1942 1550 85 + - 21 0 79 - 2770 Males: 35-39 0 76 0 20 48 S0 40-44 79.5 77 . 61 36 45-49 85.5 78 67 68 42 50 50-54 220 77 169 128 55-59 397 75 298 237 37.5 25 60-64 741 75 556 412 65-69 1089 76 827 730 32 25 70-74 1936 76 1472 1150 75-79 2639 77 2024 1850 25 10 80-84 4374 81 3543 _950 85+ - 14 10 86 - 4700 (Hirayama. 1984a). The 5% of ever smokers who were as- sumed misclassified as never smokers were assumed to consist of 23% light current smokers and 77% long term exsmokers. The excess risks for current. self-reported smokers were re- duced by 2/3 to yield relative risks for misclassified current smokers and by 11/12 for relative risks of misclassified exsmokers essentially as was done by Wald a al. (1986). This resulted in misclassified ever smoker relative risks of 2.4, and 1.85 for males and females in the U.S. and U.K. and 1.5 and 1.25 for Japan. Worldwide misclassified smoker relative risks were then calculated to be 1.8 for males and 1.6 for females based on the proportion of ••western" and "eastern" cases. The false «lativt;', ritks shown on lines 2 in Table S were then calculated using t'he formulae in Wells' unpublished work. For female cancer other than lung, the smoker relative risk of 1.05 was taken from Hammond (1966) and used as is since the effect is too small to make any difference. For ischemic heart disease the ever smoker relative risks from Hammond Table A4. Annual U. S. female heart deaths from passiye smoking. Relative Risk Relative Neversmoker Exposed Constant at 1?3 Risk D h R P l i Age of eat ate per 100.000 opu at on (Table 6) Excess Declining Death (Table A3) 1000's D.R. Deaths RR Deaths 35-39 2.0 5781 0.38 22 4.0 91 40-44 4.4 4252 0.84 36 2.0 97 45-49 10.0 3423 1.91 65 1.32 85 50-51 23 3355 4.4 138 1.17 114 55-59 Sl 3495 9.8 344 1.17 265 60-64 113 3228 22.1 713 1.17 548 65-69 240 2912 47.7 13$S ', 1.17 1062 70-74 480 2030 97.2 1973 ' 1.17 1505 75-79 870 1472 180 2647 1.17 2010 80-8i 1550 547 334 1828 ' 1.17 1374 85+ 2700 100 607 607 1.17 451 Totals 291 30595 31.9 9768 ' 7602

- ~ Adult mortality from passive smoking 261 • Table A5. Annual U. S. male hean deaths from passive smoking. Relative Risk Relative Neversmoker D Exposed P Constant at 1.31 Risk eath Rate opulation Declining Age of 1,, pe r 100,000 (Table A I) Excess Death (Table A3) 1000's D.R. Deaths RR Deaths 35-39 20 3815 4.9 187 5.2 780 40-44 36 2980 8.9 265 3.0 879 t 45-49 68 2440 16.9 411 1.92 929 S0-54 128 2660 32.1 724 1.42 951 SS-59 237 21SS 59.8 1289 1.28 1201 60-64 412 2054 105 2157 1.28 2009 65-69 730 1695 189 3195 1.28 2972 70-74 1150 1099 304 3341' 1.28 3103 75-79 1850 633 S00 3162 1.28 2933 80-8.1 2950 249 819 2039 1.28 1887 85+ 4700 41 1377 565 520 Totals 521 19.120 89.3 M7335 1816i (1966) were taken as 2.3 for males and 2.0 for females. The excess risks were reduced by 2/3 to yield relative risks for misclassified ever smokers of approximately 1.4 for males and 1.3 for females. These were used worldwide with Wells' un- published formulae to calculate the false hean disease relative risks shown on lines 2 of Table S. Appendix B Relative risks for all causes ojdeath and for emphysema and chronic obstructive lung disease Data relating all causes of death with passive smoking for females have been reported for four prospective studies to- talling9537 cases as shown in Table B 1. The combined relative risk is 1.165 with 95% confidence limits of 1.11 to 1.22. The only male data available are 75 cases from Gillis et al. (1984) with_a relative risk of 1.0 so no male analysis was made. The calculation of the total number of female deaths from all causes for passive smoking is shown in Table B2. The total. 34.164. is considerably larger than the total for cancer plus heart of 19.359 shown in Table 7. Some of the difference is due to uncertainties in the calculations, but other causes of death that might contribute to the all cause total, based on data in a private communication from Dr. Hirayanka, are cerebrovascular disease, other heart disease, diabetes, and ulcer. Hirayama (private communication. also reported preli- minarily at Sth World Conference on Smoking and Health, Winnipeg, 1983) provides data relating deaths from emphy- sema with passive smoking in women. His relative risk. based on 106 cases ls ;.3 with 95% confidence limits of 0.85 to 2.05. Kalandidi et al,. (1987) report incidence data for chronic ob- structive lung disease based on 103 cases with an adjusted relative risk of about 1.4. l,ee et al. (1986) report incidence data for chronic bronchitis from spouse exposure. Based on 17 cases the adjusted relative risk is 1.22. A weighted average of these three relative risks would be about 1.35. The only neversmoker death rate we have is from Hammond (1966) for emphysema at 2 x 10-s. Assuming 76% exposure, the excess death rate for passive smoking using Eq. (2) would be 0.55 x 10-s and the total deaths for an exposed population of 30.6 million would be about 170. Even if this number is doubled to take into account deaths from forms of chronic obstructive lung disease other than emphysema. it is still far below the total for cancer and ischemic heart disease. Table B1. Female relative risks for all causes of death from passive smoking. l T All Exposures Mantel Trend Locale ota Cases RR 95% C.L. 1-tail p Cohort Studies: Hirayama (1987) Japan 9106 1.17• l.1?- 1.23• 0.01X101 Gillis cr al. (1984) Scotland 102 1.45 0.91-2.30 Garland ci al. (1985) California 79 1.06 0.65-1.73 Vandenbroucke et al (1984)° Holland 250 79 0 57-1 0 09 . . . . -~.•--•-- Combined Chort: 9537 1.165 '' 1:11-1.2: 'Dr. Hirayama (private communication) provided the data necessary to calculate these items. 'Data from 25 year follow up. Relative risk was 0.89 (0.50-1.62) for 15 year follow up. This study is weak in that exsmoking women were included among the "nonsmokers." and rionsmo{;ing women exposed to cxsmoker husbands were included in the '•nonexposed." The weakness of the study is emphasized in that the smoking women had a lower overall death rate (33.4rXc) than the nonExposed nonsmokers (38.1rr).

262 A. J. Wells r Death rates for txposed and not exposed populations were obtained by dividing the observed deaths in each category by person years which were equated to the mid-point populations multiplied by the years of followup. The rate difference was then obtained by subtracting the nonexposed death rate from the exposed death rate. Variances and weights were calculated by Rothman's formulae. The combined rate difference was obtained by summing the weighted rate differences and di- viding by the sum of the weights. Confidence limits (95%) were equated to the rate difference s 1.96 (variance)". The results of these calculations are summarized in Table Cl. The cohort data were also combined using Program 7 of Rothman and Boice (1982) with results essentially identical to those shown in Table CI for direct pooling. The relative heterogeneity of the relative risks (RR) vs. the rate differences (RD) can be approximated by considering the range of RR- I versus the range of RD. The range of RR-1 is from 0.16 to 2.6 for a factor qf 46.3. The range of the rate differences is 3.7 to 262 or a fac+tor of 71. The ratio for the two large studies. Helsing et a!. (19$8) and Hirayama (1984b), for RR-1 is 0.24/ 0.16 = 1.5 and for RD is 20.7/3.7 = 5.6. The 95% confidence limits for the rate ratio combination is tighter than for the rate difference combination. Also. the Hirayama study dom- inates the rate difference aggregation much more than in the rate ratio aggregation, providing 64% of the combined weight (last column of Table Cl) in the rate difference case vs. only 17% of the combined weight in the rate ratio case. n Table Cl. Rate difference calculations for female ischemic hean disease. Relative Risk from Table 4 Rate difference x 14` Weights RD x Total Cases RR 95% C.L. RD 95% C.L. for RD x 10•' weight x 10'' Cohort Studies: Hirayama (1984b) 494 1.16 0.9- 1.4 3.7 +-2.1- 9.6 1110 41.4 Gillis et al. (1994) 21 3.6 0.9-13.8 169.1 y 3Q.7-307.6 2 3.4 Garland etal. (1985) 19 3.5 0.9-13.6 262.2 36.0-a88.4 0.8 2.0 Helsing a al. (1988) 988 1.24 1.1- 1.4 20.7 _ '- 0.2- 41.6 ..,....~.~.. 88 18.2 Combined Cohort 1522 1.23 1.1- 1.4 5.4 70.2- 11.1 1201 65.0 'j.able B2. Annual U.S. female deaths from all causes from passive smoking. Decrement Corrected Neversmoker Relative Risk due to heart Neversmoker death rate Constant at 1.165 death at ath d t ct d i l P F i r e 1963-8a e ra e at enrolled age corre e to age of death on opu at tirposed ract on of population Excess pet100.000 per 100.000 per 100.000 1000's exposed D.R. Deaths 35-39 136 3.6 132.4 120 5781 0.94 17.1 991 40-44 178 6.4 171.6 155 4252 0.92 22.2 944 45-49 254 8.2 243.8 212 3423 0.89 30.5 1044 50-54 352 16.8 335.2 300 3355 0.87 43.3 1452 55-59 561 38 523 445 3495 0.84 64.5 2254 60-64 867 87 780 675 3228 0.77 98.8 3190 65-69 1492 171 1321 1070 2912 0.70 158.3 4609 70-74 2585 346 2239 1830 2030 0.59 275.2 .5586 75-79 4790 576 4214 3250 1472 0.49 496.1 7303 80-84 8408 832 7576 6000 5i7 0.29 944.8 5168 85+ - - - 10.000 100 0.10 1623 1623 Totals 30595 111.7 3416a Deaths per million total population 143 Neversmoker Death Rates from Hammond (1966) at Age enrolled age Range per 100.000 Lee eral. (1986) report data on chronic bronchitis life long nonsmoking in males exposed to a smoking spouse. Based on nine cases the adjusted relative risk was 0.34. However, for general exposure (4 cases) a positive relative risk was ob- served. No analysis of these data was attempted. Appendix C Rate difference model for assessing female ischemic heart deaths from passive smoking A rate difference or absolute risk model was investigated for female ischemic heart disease in order to compare it to the relative risk models in ability to translate experience from one type of culture to another. Female ischemic heart disease was chosen because considerable data exist and because heart disease is the largest contributor to total deaths. Also. the relative risk model seems already to be well established for lung cancer (Wald et al., 1986; Blot and Fraumeni. 1986) so a comparison in another disease category appeared to be ap- propriate. Data from the four cohort studies (see Table 4) were com- bined using the direct pooling equations described on page 183 in Rothman (1986). The two case/control studies were omitted. Although their combined rate difference was essen- tially the same as that for the cohort studies, no good way could be found to combine it with that from the cohort studies.

t Adult mortality from passive smoking 263 Table Dl. Regional particle deposition from mouth breathing of side stream smoke. Aero- Relative Fraction of inhaled particle mass deposited" Mass i V l i d d dynam c o ume Mass te as epos diameter Cube of Relative (weight) Distribution mouth tracheo- % di total µm diameter eorjcsntration' per 0.1µm °k throat bronchial alveolar mass inhaled 0.20 .008 1.5 0.006 0.3 0 0 0.13 0.04 0.25 .016 6.5 0.051 2.4 0 0 0.122 0.29 0.30 .027 10.0 0.135 6.4 0 0 0.115 0.74 0.35 .043 13.0 0.280 13.2 0 0 0.108 1.43 0.40 .064 13.0 0.416 19.6 0 0 0.10 1.96 0.43 .091 6.5 0.296 14.0 0 0 0.105 1.47 0.50 .125 3.5 0.328 15.5 0 0 0.11 1.71 0.60 .216 1.25 0.270 12.7 0 0 0.115 1.46 0.70 .343 0.5 0.172 8.1 0 0 0.12 0.97 0.80 .512 0.25 0.128 6.0 0 0 0.13 0.78 0.90 .729 0.05 0.036 1.7 0 0 0.14 0.24 1.00 1.0 0 0 0 0 0 0.15 0_00 2.118 99.9 11.08 •From Hiller u a!. (1982). Fig. 1. "From Heyder (1984). Table 1. 250 cm'/second mean flow rate. 4 second breathing cycle. This domination of the rate difference model by the Jap- anese study is evident from some rough death calculations. Use of the combined rate difference (5.4 x l0-`) with the exposed female population from Table A4 (30.6 million) yields total deaths of 1.652 compared with 9.768 calculated from the constant rate ratio model. When the rate differences are plotted against age of death and weighted accordingly it is found that the "western" rate differences increase sharply with age whereas the Japanese rate difference stays constant at about 4 x 10''. Constructing a weighted average of these •'western" and "eastern" death rates for each of the 5 year age ranges and multiplying by the corresponding exposed pop- ulations yields a total of about,2,100 deaths compared with 7.602 in the se;ond relative risk model. Use of the Japanese data alone yields about 1.200 deaths. Use of only the ••west- ern" data (Gillis et al.. 1984; Garland et al.. 1988; Helsing et al.) at a constant rate difference yields 7.950 deaths while use of "westerA" data with the rate difference varying with age yields about 30.000 deaths. Thus. the death calculations using rate differences are quite volatile. Also, it is evident that with the rate differences it is not feasible to carry over the "eastern" experience, in ischemic heart disease at least, for use in a"western" setting. Accordingly. it was concluded that'the absolute risk model is not as suited to combining risks for passive smoking as the relative risk models. Table D2. Regional particle deposition from nose breathing of sidestream smoke. Aero- d Fraction of inhaled particle mass deposited" Mass deposited as g~r of total mass ynamic diameter Mass distribution mouth tracheo- inhaled µm K• nose throat bronchial alveolar nose alveolar 0.20 0.3 0 0 0 0.19 0.00 0.06 0:25 2.4 0.005 0 0 0.172 0.01 0.41 0.30 6.4 0.01 0 0 0.155 0.06 0.99 0.35 13.2 0.015 0 0 0.138 0.20 1.82 0.40 19.6 0.02 0 0 0.12 0.39 2.35 0.45 14.0 0.03 0 0 0.122 0.42 1.70 0.50 15.5 0.04 0 0 0.125 0.62 1.94 0.60 12.7 0.05 0 0 0.129 0.64 1.63 0.70 8.1 0.06 0 0 V.13 0.49 1.u5 0.80 6.0 0.077 0 0 w33 0.46 0.811 0.90 1.7 0.093 0 0 41.137 0.16 0.23 1.00 0.0 0.11 0 0 0.14 0.(10 001 3.45 1'.99 'From Table Dl. •From Heyder (198a). Table 2. 250 em' second mean flow rate. 4 second brjeathing cycle. ~

.264 A. J. Wells Table D3. Smoke Particle deposition patterns in direct and passive smoking. Direct Smoking Passive Smoking DirectrPassive Entry site Particulate inhaled per day. mg. Mouth 240 Nose 2.8 86 Particle Size inhaled. µm 0.7 0.4 Particle size exhaled. µm 0.7 0.4 Retained in nose. °k 0 3.5 Retained in mouth. % 25 0 Retained in tracheo-bronchial region. % 35 0 Retained in near alveolar region.'t: 11 0 Retained in deep alveolar region. ck 9 J3 Total retained. % 80 16.5 Particulate retained, total, mg. 192 0.16 417 Particulate retained, alveolar, rrig. 48 0.36 133 Particulate retained, deep alveolar. mg. 22 0.36 61 Appendix D Dose consideratforu As noted in the text, there is a wide difference between the observed disease ratio between passive and active smokers and the ratio of cigarette smoke particulate retained by each. Also, the cancer sites appear to differ. On the assumption that part of these differences may be due to differences in deposition sites between passive smoking and active smoking, calculations were carried out to try to pinpoint these differ- ences. The calculations for passive smoking are reasonably straightforward. Stober (1984) has summarized all the uncer- tainties in this type of calculation. Nevertheless, the best ap- proach appears to be to use the data of Hiller et al. (1982) for the particle size range of side stream smoke, centering around 0.4 µm, and the mathematical lung model of Heyder (1984) for inert particles. Integration of these two data sets yields a, distribution of deposited weights by particle size for mouth breathing (see Table D1) which, when summed. yields exactly the total deposition observed by Hiller et al., (1982) indicating that the Heyder model holds for passive smoking. The same inhaled particle size distribution can then be applied to Heyder's nose breathing case (see Table D2) which yields nasal deposition of 3.5% and deposition in the alveolar region of the lung of 13.0%. The model predicts zero deposition for both the mouth/throat and the tracheo-bronchial regions. From the deposition curves of Gerrity et al. (1979) (Fig. 2) for iron oxide extrapolated to a particle size of 0.25 µm (which is equivalent to an aerodynamic diameter of 0.4 µm) it appears that all of the lung deposition from passive smoking probably occurs deep in the alveolar region at generation 19 or beyond. Black and Pritchard (1984) have determined the half-time for alveolar retention for direct cigarette smoke to be 17 hours indicating that the smoke particles dissolve and clear into the blood or lymph system. There is every reason to believe that the passive smoke particles clear the same way. With direct smoking there has so far been no model de- veloped that explains the observed phenomena, namely that the inhaled particle size is about 0.7 µm. that 70% to 80% of the inhaled smoke is retained, that 15 to 35% is retained in the mouth, and that the exhaled particle size is also about 0.7 µm. The Heyder model at 0.7 µm would predict total retention of only 12%. To achieve 75% retention, the Heyder model would require an effective particle size of 6.5 µm. Main stream smoke is known to agglomerate, but if it agglomerated to 6.5 µm, the exhaled smoke, according to the Heyder model, would be about 6 µm. much too large compared to that observed. Mitchell (1962) observed that direct smoke particles grow in the mouth to. about 1.15 µm and that the smoke exhaled froM the lung after a 5 second retention period had a mass mediari diameter size of 0.65 µm. Let us assume that the 0.65 µm part of the smoke follows Heyder's model and that 20% of the total smoke inhaled was exhaled, all from the 0.65 µm fraction. The inhaled part of the smoke corre- sponding with the 0.65 µm part exhaled would have the same particle size and would deposit about 12%. deep in the al- veolar region. This is 12% of 22.7% of the total smoke in- haled. or 2.7% of;the total inhaled smoke. The balance of the inhaled smoke (17%) would have a larger average particle size, about 1.3 µm. Black and Pritchard (1984) found. based on clearance data, that the rates of alveolar deposition to alveolar plus tracheo-bronchial deposition in direct smoking is 0.36. Also, as nQted, some amount, say 25% of the total inlet smoke should deposit in the mouth and throat, all of which would have tp come from this larger size fraction. Sum- marizing these numbers, of the 100 - 20 - 25 = 35% of total smoke particulate that reaches the lung and is not ex- haled. 0.64 x 55 * 35% deposits in the tracheo-bronchial region and 0.36 xtS - 20% deposits in the alveolar region. We have already accounted for 3% of the alveolar deposition from the 0.65 µm particles. The remaining 17% would come from the larger particles. Based on the alveolar/tracheo-bron- chial split and usingthe curves of Gerrity ct al. (1979) it would be. expected that about 2/3 of the alveolar deposit or 11% would deposit in the •'near" alveolar region, generations 16- 18, and 6% in the "deep" alveolar region. generations 19- 21. for a total '•deep" alveolar deposition of 9%. These cal- culations are summarized in Table D3. Just what the mechanisms are for so much direct smoke deposition remains unclear. Certainly impaction and sedi- mentation (the Heyder model) do not account for it. Stober (1984) suggests that electrical charges in the newly generated smoke particles (se ~Aetandri et at., 1983) may account for some of it. Arlothe>~possible mechanism is the cloud settling phenomenon as de4cribed ~by Fuchs (1964). Whatever the 'trt charlisrtt, a reasonably clear idea of the regional deposition ~tjttertts from direct and passive smoking a,

•,, . _.. ... ..~~~~. num passY.•e smoking can be obtained as shown in Table D3. The nasal deposition from passive smoking could account for the observed nasal sinus cancer. Also. if the observation of Balin er ol. (19$6) is correct that there is a direct passage for toxics from the nose to the brain. it could also account for the observed brain cancer. In the deep alveolar region the ratio of direct to pas- r- :hi sive deposition is much closer to the inhaled ratio than to the "total retained" iatio. It is from the deep alveolar region that the smoke panicl,es are solubilized and cleared into the blood and lymph systems possibly to cause cancers of the liver, breast and endocrine glands, leukemia. lymphoma and ar- terial plaques.