Document kLEMm8YRex5J8w61o2pBkjzJ

FILE NAME: ZD^D/ DATE: DOC#: ^D/ DOCUMENT DESCRIPTION:hZZZ dZZ>Zt>Z&E& ..-~ Report - critique Braun-Truan False Negative Findings Which Lead to '. ,,.,. Limitations "' 1950 was - short, t_o.o. _..- si}{. __. - follow-up of the cohort eriod for 1ung can- ---, I. The period ohf requirements of the latent tPhe time the study years, to meet t e ~edical knowledge then at that although cer. It was basic confirmed from many studies, period, was conducted, and following a Short latent occupational cancer can occur majority Of l ung cancers occurs usually the clustering of the usually an interval of 25 after an interval of 20(Fyoeraresxaomrplme,orein, the study of chromate or 30 years or more. f the lung cancers occur after an interval workers, the majority O extend to 42 years.) The long latent. dJ.:. of 26-36 years and may others i'n asbest osw~-J period has been observed by Selikoff and occurred after an workers, where most of the lung cancer cases interval of 20 years. tudy, the cohort was of those who were t In the Braun-Truan ho had S worked five years or more--whic<h.Ltw..o_u~ld-tv.~ 1 ~\ working in 1950 w years for the cohort as a whole. ( r mean a period of 11 sign of the study limiting the period of - In essence, the de d a built-in limiting factor subsequent observation to six years, haeverely- limit observations in the study--;,lhuicnhg wcaonuclderpwrhi:ch: n reqeuisred a much longer latent a fundamental - ppeerrtiaoidn.ingThteo limited follow-up period represented findings ~%i~ the study, which secvaeuresely thliemiintetderavnayl poof stiitmivee of observa- ired ! , rtieolantifvoellotwo -ulupngwacsantocoer-s-hboert for the interval in years requ for the development of the majority of the lung cancers. l"/ - 2- I / I This was evident to shown in the designation lung cancer cases, shown the investigators themselves--as clearly of years of employment for each of the in Tables 6 and 7 on page 642 of the published paper. (Example: Excluding one case of 16 years, of - the total of 12 lung cancer cases, 11 had an employment of 20 or more years, which means that the interval of time for these lung - cancers since start of employment was 20 or more years.} There is no ~ recognition or admission made in the Summary of the paper ._,,,,. that the ,,__,, design of the study had a self-limiting factor to make such observations less meaningful. In essence, the design of the - study increased markedly the probability of false negative find- ings -.._ and increased the probability that the investigators would come up with ar.ti-f-icial, incorrect, low association of lung cancer and asbestos exposure. Further, the investigators state that 133 members of the cohort could not be found. If the 133 were found and only one or two lung cancers had been located, the conclusion of the study-even in its limited state--would be in the direction of positive rather than negative findings. Jit~" v\,\.'~ j. \ { ") ...r \ r" II. The second limiting factor relates to ob~us.questionable and inappropriate classification of the cohort' by categories of degree of exposure into~!, II, III. - (,,, Evidence of this~classification of exposure is reflected in . ,,. '\.b--. . . 1.) both the pre-publication report and in the published report. ( I i_cT 1. v., f On page "" 33 of the pre-publication report, tables show the ' --- ~ncers years of employment for the nine proven lung and three ,. ~ ~ ~ ~~ ~ ~ ~ ~ -t~ ~ ~M~~ ~ ~ VV1.'t {,._,..--/ 11 (h, I .__,,; (kl ~ ~I f ,,..,...,_,. L......._ J:B, I 3 /:_:- ~ ~ ,~-0~.D ~~ ~+ ~.....~ ,,.~~ c---/~~ I ~,,cI _) ~9~~~~ ,__ ,... '1.- n:;_._ y t-. h-t ~ ~ ,._; ~ r---- ~ ~ y- ./-- ~ !.-<. ,,._..J.,.,._ ~ yf<?~ ~ ~.__) ~ ~ ""' ,-<"~ ~~ fj ~t~ ~fA1'!~ /(~~~ ti-~ ,_,~uJ; ti~~~~'(' - 3- "suspected" primary cancers of the Page 33 '\\ ~~ Proven ~ Asbestos cohort lung, classified Thetford by exposure. Suspected Exposure t_ Category I " Exposure Category II 34 years, !Z years , ~~~years 32 years rt years 22 years 30 years f Exposure Category III years -v'> 283 years 42 years \ \ I ~ 32 years JI 33 years ~ wo~~e.::__ The table demonstrates that for all the (who had lung \ ' ~ cancer)A those with th<:ongesYand therefore 6.i.she~tperiod of ~ employment exposure to asbestos, {j)years an.('3Yyears in the ~ asbestos~hort, the~tegory Exposure~ were a:.:!;!ned to of Three of the total of nine proven lung .cancer cases, ~}~ gf - - ~h had ~ears or more exposure employment, were classified as Category I. For Category II classification of exposure, the highest exposure occurring in terms of years of employment of all categories ~~ and all lung cancers was 4....2..._, years in the Thetford mines. All four lung cancers had 22 or more years of employment; three of the four had 26 or more years of employment exposure. ---- In the comparison -~ of the fou,,r,.:.lung cancers in Category III with Category~f-or both asbestosrcohort and Thetford mines, the Category I had equal or higher number of employment exposure years in~~: ~c()!"P.~sons It J process the with Category__;;;r. is readily apparent that there are Q?sic~in whatever was used in the assignment of exposure categories, as evi- denced by the categories assigned to the lung cancer cases. - 4- Anyone at all acquainted with work processes would recognize that the constant dust exposure each day, week, month, for 25 or more years for the miners represents a~emendous accumulatioiyof dust exposure over those years. Even employment exposure of 16 years, the lowest number of years for any of the lung cancer cases, would I represent a tremendous cumulative dust exposure. In industrial studies, the usual classification of employment exposure is 0-1 years, 1-2 years, etc. But never in the history of industrial medicine has dust exposure of 34, 37, 32 years been classified Category I, as lowest exposure. - The ,; contradiction in the classification exposure comparisons ~ J - - of the lung cancer cases in I, II, III relative to number of years employment exposure, make the analysis of such data unreliable - <:::::: - and / therefore the conclusions unreliable. In order for any one to really be l\~4~"4~ exposure~ it would have been necessary r- measurement the dust concentration for able to designate work to know by air sampling and each week, month, year for the 30 plus years, for each work area. Sine~ such measurements ~ .<....~ ,... were made, and in face of the great many years of employment in Category I, it must be concluded that the dust exposure categories - - \ made cannot be justified and are misleading, and that there is a -.--- basic/weaknes3 relative to the classification of the - work exposure to asbestos. This is important because the authors rely upon this classification of exposure as the basis for ~'\.]., their conclusion of negative findings, because there was no correlation, f\ no increase in death rate for lung cancer by increa5e in exposure l - 5- categories. begin with, Obviously, if the classifications are in error to / i the correlations themselves are meaningless. ---~k.v-+r~f F-A,;..c . ,. r Vvv-,.,.. <- . \,/v"-r-v \,: '. , III. Another built-in limitation in the analysis of the data f\. and therefore limitations of the findings, relates to comparison of data in the pre-publication with that in the published article pertaining to the~lutio~f the cohort, as shown in the percen- tage distribution by age and percentage distribution by length of f employment. # In the 2:,2 lung cancer cases, @had employment of _2_o_o_r_m_o_r_e years. Only one of the 12 had employment of less than 20 years. l''---"' - IE~( out of n~~ ~ lung cancer cases had over 20 years ('~- dura- v tion of employment, and s.e..v-.en out of the nine had 25 or more years - - of employment. This means, according to their study, that the \ ~ increased risk for lung cancer in their particular miner cohort, / F ... ,/ occurs after 20 years of employment. pageTh~e flimthietaft,i!o!.nPrfiantc.t,or:,aibsleth2e--7d7il%utoifonthefacastoberstaos~ sh-o~owhnoro~n..'.~~~ ,, 67% for Thetford ( , ) '--\" mines had less than 20 years of employment. It \..--~' ~ ... .(. ...i ~. \i-....--->- .. is obvious that a-ar1ution factor of 70%, in the cohort of employ- ees, !\ tremendously lessens - ;1 l'LiJ "'' -.t.. the possibility'1of any observations pertaining to lung cancer, which as previously shown required 20 years duration of employment. /',./. 1, L) - 6- cigarettes or more a day, which is not the classification defini- tion of the major published studies pertaining to cigarette smoking and lung cancer: Richard ~~--5~ o'- more a day; Wynder and ... - - - - .......... Graham--35 or more a day; Sodowsky and Gilliam--41 or more a day; -------~- Bres low--40 or more a day. --- - It is obvious th, at the criteria for heavy smoking, stated as 5 cigarettes or more a day by Braun and Truan is incorrect and therefore the analysis that was conducted and reported in the publication relative to smokers (5 cigarettes or more versus none) ,_..,.,.. are invalid. When the designation of heavy smokers is set at 5 5? (" ~ Iv. ' ~ cigarettes or more as was done in NW.s study, it mixes up the truly heavy smokers, those of 40 cigarettes or more a day, with the moderate smokers and very light smokers. Further, there is no way to determine how the smoking his- - tories were obtained--no information relative to age at start of - - smoking, nor duration of period of smoking. Again- in Ta-ble 4.q..,o...,f._ 'lt-hq e pre-publication report, the percen- of smokers is shown to be: ( ... Asbestos....- Cohort Thetford Mines 7ft @ Smokers 85% .( , ~ However, in Table ~~~-' ~ung cancer rate of the Cohort Asbestos r ,...." "~"""r~ Miners is 22.1/100,000 .. while the Thetford Miners proved 27.3/100,000. ;_v-J\ vv".,;;_,hv \, ) ' - The total suspected is 41.0. f\. ~ According to the table, the asbestos miners cohort, with 85% ' -- smokers, had the lower lung cancer death rate, 22.1 compared to - - - \ .. Thetford miners which had the h...igher rate for lung cancer of 27.3, /.i /\_\.,~ --- ).!t/\~ (\~ - 7- with the lower percentage of smokers, 74%. According to these \~ tables, the more you smoke the less is the lung cancer rate. They ~ . do not bring this out in the analysis or in the finqings. ,.(_. ._ -~)~y..L)o!:r~~,.---.-~1...)'':c,.., ,,1 ,,..l..... L. .--,,~..,,_ vi~e,_...."'l /Z,<....A~-~ I-... -. .1. ,l.._.._V>--u1"'- 1--v- ,.--'",......._."'"'\.A. - l::.q..,,~--_L 7 ~~ <,,f11~I,r-- u~ -t'f ---\; ~,.\.'-'.i t ~: j - - - ' t-: -~ ~ 1-'-<--T' /t-C..-<-~::::"4. ~ ._,., J,,.-._""~-__.._..z._~1 "'7 = tLr-+--;f';\ There i' s !nother l1' m1' ti'ng f actor, and t hi' s re1a t es to the "combined"~the of the averaging effect when the two indi- vidual mining facilities are combined in the presentation of the death rates. The compari~on of Table 20 in the pre-publication ~~'<S - report with Table 16 of the published report illustrates the problem of the averaging effect, where a higher rate is submerged in the average combined rate. ';,\ In the prepublished report, Table 20--asbesto~cohort had a 1' rate 22 .1 proven lung cancer and Thetford miners had a rate of 27. 3 ~~ and for the total lung cancers 41. O. When they combined the proven _,.i ~~ ~\ " - LM '.MA ,..~,_,._;:i ~~')"-i.J'< , cases of 22.1 and 27.3, the combined rate became 25.3 which is less - ............ /\ - - ~ u....~.. - than the higher rate observed of 27.3. - It is that average combined ~Iv1 ~k&~~' '- l:v er which is compared to the Province rate of 22. 5. In_;ssence, - f ,, (, \J \ the higher rate of 27.3 is submerged in the average of 25.3. - ~~~ - (1..---~---~-- Similarly, the higher rate of 41 is submerged in the average of 33. 8 would be statistically significant compared to-;;. 5. /\- This is mentioned because in the published document, it is stated that 33.8 is close to being statistically significant. Obviously, - rates above 33 are going to reach that point. By using the combined figures as was done in that report, it lessens the difference between the observed and the control group, J which is the Province rate. Whenever an investigator lowers the numbers in the observed group, this of course lessens the chances of noting any positive findings.  - 8- V VI. Further, in the pre-publication, page 29, TabJ,.e the - ,~ distribution,.,,by exposure category of the l-L~ asbestos mining cohort and the Thetford area differ substantially and therefore, any combination do=ne in the Exposure Category of the two would be p ~ 3 study. In Asbestos City in_aPfI:'opriat=.; This was actually 0,~i-f 1'M Y \~\ j Thetford Combined .><=; I 969 I 43% II 564 I 25% 1062 I 29% 1586 I 43% ( 34% ~y<Y\'~ ~/ 36% III 735 I 32% 1037 I 28% 30% Unknown 5 x 0 100% 100% 100% It is noted that in Exposure Category I, J{ asbestos miners cohort had 43% and Thetford miners.had - u;- --- Exposure Category II: asbestos - ,. - - When you combine the two mini1ng 29%. The reverse occurred in cohort had 25% and Thetford 43%. facilities who have such marked differences in percentages, by exposure classification, the inves- tigators are actually mixing weighted populations in different categories and then combining them as one. It is obvious that the use of the combined exposure percen- tage is not accurate because it submerges important differences. Therefore, the exposure group combinations and designations are misleading. ~ In the lead-off to the Braun-Truan Report, the authors try to conv9y the imprGssion that the prior epidemiologic~l work or - 9- prior reports relative to asbestos and lung cancer had certain limi- tations, and as a means of demonstrating that, they were going to overcome the limitations by having a total population that was followed over a period of time. Their critique in effect said that the prior publications, because they related to autopsies of indi- viduals and groups of individuals, were dealing with selective groups and therefore, in their terms, their study would be much better because of the fact that they were going to take a total population and study that total population. What they did not say :nd what they did not include in theii analysis was an analysis of their own data in Tables 6 and 7 of the published report. Table 6 refers to proven cases of the primary cancer of the lung; it specifies the exposure, meaning the years that the indi- - --- vidual was employed; it specifies whether the individual had an autopsy; and the column to the right specifies whether there was an asbestosis or not. Of the~ cases of proven lung cancers, there were~ autopsies and there were !our cases of asbestosis, which gives you approximately a percentage of 57 percent of lung cancers having asbestosis. Moving to Table 7, and adding to Table~ the suspected lung cancer cases and the additional autopsies, you find eight autopsies - and five --- observed cases of asbestosis, for a percentage pf 62 J~ ~ ~'\ <::~+.....,,.,. - percent} What has happened here, and what Braun-Truan unfortunately ~neglected to emphasize, was that they proved and confirmed all the ~ prior studies of the relationship of asbestosis and lung cancer by overcoming the difficulties they had previously cited other authors had had, by using the method which they called a representative I - 10 - -sample, a representative population of all the asbestos miners, which they took, and they found all the lung cancers in their particular study and determined those who had auto sies &i) lung cancers and found percent in one category er cent - in the other -14 percent an Consequently, this was much higher than even the 16 ., percent and 17 percent and 13 percent previously --- -- r_e.,.p....o. rted by o authors, which were significant in comparison ...... - to the percent ge of lung cancers observed among individuals ex- posed to silic ~ ~ ~"""" v-.,...J -.. - tJ--1-~~ ~~, ~ ~~ ~~ ~ ~ ~ l~ ~ (!...~ ~-<. t-v::-L_ ~~~~~~~~ (f~ g~~~~~ --- ~ I ,he~ ~ ~ ,_,(_vi..A...-LJ. . , ~ C,~~ ~ ~ ~ [}-~ d~'-" ~~ ~ u,y' ~_.;'\; TL-I ..___.I t I ~ ~~~ 26 Dr. Mancuso - Direct 81 2 3 MR. HENDERSON: No. I think that we 4 want to finish it. You asked him about 5 Braun-Truan, and he has a response for you 6 that's as complete as he has it; and he 7 wants to do it and I want him to do it. 8 Q All right, Dr. Mancuso. Did you observe anything 9 else in comparing the draft Braun-Truan Report 10 with the final published report? 11 A Yes, I dia(Gm referring now to the published 12 document of the Braun-Truan Report, and I'm 13 ~re7 fer~ ring 14 ( 4 specifically to Tables 6 and 7. I'm it within the following context and for 15 the following reason: In the Braun-Truan Report t_ tt: 16 lead-off of his document in the preparation .;0: .0"..' 17 to try to convey the impression that the prior . 18 epidemiological work or prior reports relative 0 ::! 0 19 to asbestos and lung cancer had certain limitation ... z z ~.. 20 and as a means of demonstrating that he was going .ci u 21 to overcome these limitations by having a total < ~" 22 population that was followed over a period of 23 time, his critique in effect said that the prior 24 publicatio~s, because they related to autopsies 25 of individuals and groups of individuals, he 27 ( 2 3 4 5 .J~ 6 7 ~'\l 8 9 \. I 10 Q 11 A ~cl 12 \ 13 (. 14 15 16 ..: 0... 17 ..0 18 !: 0 .; 19 .; z 0 20 21 22 23 24 I l 25 Or. Mancuso - Direct 82 implied and stated that this was a selective group and therefore, in his terms, his study would be much better because of the fact that he was going , population: but -% not1 say and what he di / include in his analysis was an analysis of his own data on Tables 6 and 7. Is that in the final report, Doctor? His final report published in the Archives of Industrial Health, and in Table 6 it refers to proven cases of the primary cancer of the lung, it specifies the exposure, meaning the years that the individual was employed, it specifies whether the individual had an autopsy, and the column to the right specifies whether there was an asbestos s or not. In looking at that table, Table 6, showing nine cases of proven lung ca~n'caeurst, oopfsie those nine lung cancers there were and there wer~cases of asbestosis, which asbestosis.~~~~ gives you approximately a percentage of 57 percen of lung cancers had If ,, you move down then to Table 7 and you add then to Table (, ~ 7 the sUS?ected lung cancer cas~s '' ( 1 28 2 6 7 8 9 /\~\ 10 11 12 13 ( 14 15 16 =:I 17 ~ " .."0 18 l? 0 19 20 21 22 23 24 I \ 25 Dr. Mancuso - Direct 83 and you add then the additional autopsies, you ---- find eight autopsies cases of asbestosis, and for observed cases of five a percentage of 62 percent. So what has happened here and what Braun-Tru had ~ortunately neglected to emphasize was that he, ~had ~and c~nfirmed all the prior studies of the relationship of asbestosis and lung cancer by overcoming the difficulties that he had previously cited the other authors had, by doing the method in which he F? said was a representative sample, representative population -study and determined those who had autopsies of the lung cancers and f ouI([" 51lper~~~~ in one ~s category and. @~e~~~~r. Consequen ly r this was much higher than even the 14 percen~_an :1:e6.....--p;;..e-rcent and 1.7....--p--e, rcent and 1..3.....p.,._er_ce_n_t _pr_e_v_iously reported by other authors, which were significant in comparison to the percentage of lung cancers observed among individuals exposed t_o___s_i_,l._i_ cosis J~\ \\1~