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te f c M f iw - Y ** 1954. bIES FOR THE TEAR 1955. T exglan axd Wa ies TH-M. Stationary Office. Anti. n , l . Acad. S c i., 132:519-525, 1965. neoplasia among insulation workers in the UNITED STATES WITH SPECIAL REFERENCE TO INTUA-ABDOMIXAL NEOPLASIA E. C. Hammond American Cancer Society; Now Tori:, N. Y. I. J . Selikoff, J . Churg T ie Mount Sinai Hospital, New York, N . Y. Before presentla s the weaSUiWe tIfilesi in our study of insulation workers, we we'believe to be M alignant neoplasms produced by exposure to chemical agents o r ioniz ing radiation typically have a long latent period. T hat is to say, there is a long delay between first exposure and the appearance of the neoplasm. In th e case of carcinogens which can be eliminated from the body, re peated contacts over a long period of tim e may be required. However, in the case of agents which are not eliminated, exposure of the tissues is continuous from tim e of first exposure. The probability th at neoplasia will occur and how soon it appears generally depend upon the degree of Now let us consider the effects of exposure to an agent which can pro duce neoplasia but which can also produce some other type of disease. results in death from some other disease w ithin ten o r fifteen years, then, because o f the long latent period, it is very unlikely th at neoplasia will result from such exposure. In these situations, the outcome depends in p art upon the tim e required to produce the other disease in relation to the tim e required for the de velopment of neoplasia; and th is in turn depends upon the degree of ex posure. Of equal importance is whether or not th e other disease can be cured, o r death delayed. An historical review of the literatu re from th is point of view is most interesting. All of the early reports apparently concerned workers who were very heavily exposed to asbestos dust. This was long before the development of the sulfa drugs and antibiotics. Pulmonary diseases including tuber culosis and pneumonia were among the leading causes of death. Life ex pectancy in the general population was fa r shorter than it is today, and a relatively small percentage of people lived to an age where the incidence of cancer becomes high. (r , In 1906. A uribault reported the results of w hat was probably the first study o f m ortality among asbestos workers.* H is account is interesting. 519 t .------------------------ ---- fp s SI "/H& '-Y' i \ . WX- 520 Annals Hew York Academy o f Sciences In 1890 an asbestos spinning m il and weaving factory was established in the neighborhood of Conde-sur-Noireau (Calvados). During the first five years o f operation there was no artificial ventilation and the employees were heavily exposed to dust from the looms. According to A uribault, fifty workers died during this five-year period. Furtherm ore, th e director, previously owner of a cotton mill, had recruited seventeen of his form er employees and "sixteen of them were wiped out by the Chalkosis." In 1918, Hoffmann was able to present some data from the industrial experience o f th e Prudential Life Insurance Company.1From 1897 to 1914 there were 13 deaths o f asbestos workers and three of these were a t tributed iso pulmonary tuberculosis. I t is of interest th a t nine o f them IS asbestos workers died under the age o f 44. This is in contrast w ith a much older average age a t death reported fo r potters, rodders, marble workers, and stone workers. Hoffmann notes that "in the practice of American and Canadian life insurance companies, asbestos workers are generally de clined on account of the assumed health-injurious conditions of the in dustry'-" He also quotes E. h . Collins (Annual Report of the Chief In spector of Factories and Workshops for England and Wales for 1910) as years among a staff of under 4Q workers in a factory weaving asbestos. Since Hoffmann's tim e, many authors have reported findings in series of cases of asbestosis. U ntil a fte r 1940, emphasis was placed upon the role of secondary infections, particularly pulmonary tuberculosis and bronchopneumonia. For example, M erewetheri, w riting in 1933 commented: Usually, th e fatal issue is determined by the onset of some acute infection w ith which the rem aining undamaged tissue is quite un able to cope: this is commonly a low grade bronchopneumonia. The same year, Gloyne* stated that, "the w riter has so fa r only seen one asbestos patient recover from bronchopneumonia." In two series of cases reported by Wood and Gloyne5 in 1934 and Stone* in 1940, bronchitis, bronchopneumonia and pulmonary tuberculosis were the .{commonest, tei^pinal. com pilations of asbestosis. However, Wood and Gloyne found two lung cancers and one cancer of the pleura in 26 "deaths of patients w ith asbestosis. ^ W ith the passage of tim e, pulmonary infections were found less fre quently and lung cancer was found more frequently in cases of asbestosis. We will not take the tim e to review the more recent literature, a large p art of which was w ritten by people present a t the Conference and ade quately covered by other papers in this Annal. It is sufficient to say th at since the advent of the antibiotics, workers have generally been saved from death due to infectious pulmonary diseases resulting as a complica tion of asbestosis. Thus they began to live long enough fo r the neoplastic effects of exposure to asbestos to become m anifest. Our study differs from the early studies in two im portant respects: ( Ham m xz x* fZc x3 *s gIPo 5 -8W l -CS8T -8561 -6WI vy- V`% - luvau ao asnvo mi -6WI mi mi ooi mi ory was estaousnea m H . P arin g the te s t five ion and th e employees lin g to A uribault, fifty ore, the director, rente of Ms form er th e Chalicosis." ,'$jjta from the Industrial \ jany.* From 1837 to 1914 ; hree of these were at,s t th a t nin e,o fSthesel3 J in contrast w ith a much marble workers, ice of American and are generally de conditions of th e in e rt of the Chief In- Wales fo r 1910) as tuberculosis in five weaving asbestos, ted findings in series placed upon the tuberculosis and :in 1988 commented : o f some acute tissue is quite un pneumonia. i so fa r only seen one t* || yne* in 1934 and Stone* `t&* >nary tuberculosis were However, Wood and th e pleura in 26 deaths w ere found less frein cases of asbestosis. mt literature, a large Conference and adeis sufficient to say th at m ne generally been saved resulting as a compliea; lough fo r the neoplastic w .: * wo im portant respects: iki; Hammond et ai. : Intra-abdominal Neoplasia 521 tn ss oN oO% to :k o <ta* co &N> ea wC94OC* 6tcO0a COs9t ohm 09 CO ei Ip*>o tcIoa o^ia C4 vgo teaa ss IO N ess n to 60 CD C4 ca to ci 0g 1to aa |Sg1 gh8 <1 8 522 Annals New York Academy o f Sciences Hami (IV The subjects had very light and interm ittent exposure to asbestos dust It is of interest as compared with the daily heavy exposure of subjects included in the old to asbestosis. Studies; and (2> We are reporting deaths which occurred a fte r 1942; th at As previously m is, a fte r antibiotics became available for the treatm ent of pneumonia and of 632 men who wt a fte r death rates from tuberculosis had been greatly reduced in this coun additional 890 men try . I t also differs from most other studies in th at we were able to trace Thus a total of l.i an entire group of workers including those who had retired and those and 1962. We ha' who had left the trade. Selikoff bad medic; The data we are presenting here is an extension of data we published end of 1962. Of th last y ear/ Therefore, we will sta rt by briefly reviewing our first report, the an additional 43 di results o f which are Summarized In table 1. The data shown here are findings shown in ", confined to the experience of 632 men. They composed the total membership of New York Local 12 and Newark Local 32 of the International Associa tion of Heat and Frost Insulators and Asbestos W orkers as of January 1, 1943. All of them were traced through December 31, 1962 and 253 of 307 Con'sex them died during th at period of time. Most of them had been first exposed to asbestos dust a t least 20 years prior to 1943. The rem ainder passed the 20-year point between 1943 and 1962; and we counted their experience T otal d eat A ll neoplas only a fte r they reached this point. TABLE 1 shows the total number of deaths and the number of deaths from selected causes during each of four successive 5-year periods. For Bronchogenic c Mesothelioma comparison, we show the number of deaths which would have been expected among these asbestos workers had th eir age specific death rates been G.I. carcinoma exactly the same as those reported for all white males in the United States during the same intervals of tim e. F irst note the total number of deaths. During the first five-year period, Upper resp irate B ladder few er deaths occurred among the asbestos workers than would have been expected on the basis of general U. S. death rates. This is accounted for G eneralized c a r by th e fact th at all of the workers were actively at work in 1943; and A ll o th er seriously ill men are unemployable. Thus th eir total death rates were low. This selective effect gradually wore off. During the last 5-year period, 88 of the workers died compared with 54.4 expected. During the entire 20- 5` j f A sbestos! A ll o th er cau yeatwpertod;-S^ asbestoT'WTirkefs died'chmpared'^vith ' Now observe the number of deaths from cancer of the lung and pleura. Of the 307 deaths During every 5-year period, fa r more than the expected number of as /5 5 per cent) were ; bestos workers died of this cause. Altogether there were 45 deaths from attributed to variou: cancer of the lung and pleura compared with 6.6 expected; a m ortality ratio of nearly 7 to 1. deaths classified by t cancer deaths > were To our surprise, these asbestos workers also had extremely high death tributed to mesothel rates attributed to cancer of the stomach, colon and rectum. The observed respiratory cancer, 4 number of deaths from these cancers was 29 compared with an expected 9.4; a m ortality ratio of 3 to 1. tosis and 10 to vario In studies of this Of the 53 deaths att ip M M P Jip M P li Sciences xposure to asbestos dust ijects included in the old :curred after 1942; th at 'J. itm ent of pneumonia and :itly reduced in this coun iat we were able to trace S\Zt%n?A had retired and those A. ion of data we published `"''I swing our first report, the ; 'he data shown here are ssed the total rwefftbsWp he International Associa ' &W orkers as of January fib er 31, 1962 and 255 of siem had been first exposed f h e rem ainder passed the counted their experience , : \ id the number of deaths ssive 5-year periods. For would have been expected ; specific death rates been ; isles in the United States the first five-year period, prs than would have been ;es. This is accounted for >ly a t work in 1943; and >tal death rates were low. - 'the last 5-year period, 88 D uring the entire 20fs4 w ith 203.5 expected. : - ;r of the lung and pleura. , ! expected number of as` iere were 45 deaths from 5.6 expected; a m ortality uad extremely high death and rectum . The observed unpared with an expected f Hammond et al. : Intra-abdominal Neoplasia 523 I t is of interest th at out of a total o f 255 deaths only 12 were attributed to asbestosis. As previously mentioned, our first report was based upon the records of 632 men who were members of the two locals on December 31,1942 An additional 890 men joined between January 1,1943 and December 31,1962. Thus a total of 1,522 were in the two locals a t some tim e between 1943 and 1962. We have traced all of them through A ugust 1964 and Dr. Selikoff had medically examined most of those who were living as of the end of 1962. Of the 1,522 men, 264 were dead as of January 1, 1963 and an additional 43 died between January 1,1963 and August 31, 1964. The findings shown in table 2 are based upon these 307 deaths. Table 2 N . Y. C. Asbestos I xsclatiox Workees 307 Consecutive Deaths J antaky 1,1943 - Acgcst 31,1964 T otal deaths A ll n eo p lasia B ronchogenic carcin o m a M esotheliom a G .I. carcin o m a U pper resp irato ry B ladder G eneralized carcin o m ato sis A ll o th e r A sbestosis A ll o th er cau ses 307 124 53 10 34 6 4 7 10 17 166 40.4% 17.3% 3.3% 11.1% 1.9% 1.3% 2.3% 2.2% 5.5% 54.1% Of the 307 deaths, 124 (40.4 per cent) were attributed to cancer, 17 (5.5 p er cent) were attributed to asbestosis and 166 154.1 per cent) were attributed to various other causes. The Table shows the 124 neoplastic deaths classified by type of neoplasm. Fifty-three (or 43 per cent of the cancer deaths! were attributed to bronchogenic carcinoma. Ten were at tributed to mesothelioma. 34 to gastrointestinal carcinoma, 6 to upper respiratory cancer, 4 to cancer of the bladder, 7 to generalized carcinoma tosis and 10 to various other cancers. In studies of this type, accuracy of diagnosis is o f prim e importance. Of the 53 deaths attributed to bronchogenic carcinoma, 34 occurred in ''"'i g p p p js p ew 5 624 Annals New York Academy o f Sciences hospitals. In IS the diagnosis was based upon post-mortem examination ami in 13 th e diagnosis was based upon histologic exam ination o f opera tive specimens. The rem aining 20 were based upon clinical evidence or inform ation reported on death certificate. 4. Churg he personally ex amined specimens from 15 of these 53 cases. J . Churg has also personally examined sections on all of th e 10 deaths attributed to mesothelioma. Four of th e 10 were pleural mesotheliomas and six were peritoneal mesotheliomas. Of the 34 deaths attributed to gastrointestinal cancer (cancer o f the stomach, colon and rectum plus one cancer o f the esophagus), 20 occurred in hospitals. Six of the diagnoses were based upon post-mortem examina tion, 19 were based upon operative specimens and nine were based upon less reliable evidence. J. Churg personally reviewed sections from 12 of these cases. Of the 27 other cancer deaths, 16 occurred in hospitals. Fifteen of the diagnoses were based upon autopsy or operative specimens, and 12 were based upon less reliable evidence. Of the 17 asbestosis deaths. 6 diagnoses were based upon post-mortem evidence and 11 upon clinical evidenceonlju. In most prospective epidemiological studies, the investigators are forced to be content w ith inform ation from death certificates plus a little addi tional inform ation. We think it fa ir to say th at in this study we were able to obtain a reliable diagnosis on cause of death in the m ajority o f eases. This does not imply th at all of the cases were correctly diagnosed. For example, the diagnosis is certainly open to question in those cases where it was based upon clinical evidence or death certificate inform ation only. This is particularly true in the case of deaths attributed to generalized carcinomatosis (w ith prim ary site unknown), and deaths attributed to stomach cancer or liver cancer. Furtherm ore, it is not unlikely th at a few mesotheliomas were missed. Indeed, in addition to the 10 deaths attributed to mesothelioma there is one lesion which looks suspiciously like this dis ease, but the diagnosis is not certain. abnormally high risk of dying of gastrointestinal cancer. However, we will refrain from draw ing conclusions on this m atter a t the present tim e. Returning to the subject of pulmonary neoplasms, TABLE 3 shows the lapsed tim e from onset of exposure to tim e of death of 57 o f our sub|ecta who died of cancer of the lung and pleura. (A few recent cases are not included here.) Not a single one of these deaths occurred in less than 20 years a fte r first exposure. The m ajority did not occur until a fte r 30 years and many did not occur until a fte r 40 years. Obviously, light exposure to asbestos dust does not lead rapidly to pulmonary neoplasia. Equally obviously, this disease is unlikely to appear Hair CAKCtNc L Les: 20 - 25 - 30 - 35 - 40+ if workers die at posare. However, for the treatm ent : of such workers. 1. Aoubault, 31. . w orkers in as 2. Hoffmaxn, X. dusty trad es Xo. 231 (Ind D .C . 3. SlEREWETHER, ] 109-118. 4. Gloyxe, S. R. h e r e in 41 550 5. Wood, W . B. & hundred cases , 8. Stoxe, J . J . 19 7. Selikoft, L J ., neoplasia. J . J m examination examination of operapon clinical evidence or urg has personally ex on all of the 10 deaths pleural mesotheliomas cancer (cancer of -the esophagus), 2 occurred post-mortem examinae+ w ew hused-iipon sections from 12 of hospitals. Fifteen of the specimens, and 12 were based upon post-mortem investigators are forced icates plus a little addi-"J this study we were able ,l n the m ajority of cases, sf rrectly diagnosed. For ,4 on In those cases where r ificate inform ation only. '.teffttributed to generalized lad deaths attributed to 4j| not unlikely th at a few *he 10 deaths attributed spieiously like this dis- H am m ond et a l.'. In tra-ab d o m in al N eoplasia TABLE 3 Carcinoma o r I.exg and Pieeea in 57 ASBESTI Wckhbs L apsed tim e fro m o n set of exposure to death 525 - - > . ->*-t Years L ess than 20 20-24 30-34 95-39 40+ Number 0 3 - -` - * 7 16 11 20 57 if workers die a t a young age due to some other effect of asbestos ex posure. However, w ith light exposure and the availability of antibiotics for th e treatm ent of infectious disease, neoplasia is a m ajor cause of death of such workers. ,, F e re n c * * 1. Aubibault, SI. 1906. O bservation reg a rd in g th e hygiene an d sa fe ty o f w orkers in asbestos spinning an d w eaving m ills. B ull. In sp . T rav ail : 196. 2. Hoffm ann, N. & L. Frederick. 1918. M ortality from respiratory dis. in d u sty tra d e s. In o rg an ic d u sts. B ull. U .S . B u reau o f L abor S ta tistic s N o. 231 (In d u stria l A ccidents and H ygiene S eries: No. 1 7 ). W ashington, D.C. Merewether, E . R. A. 1933. A m em orandum on a sb esto sis T ubercle 15: Atnr*XXO* 4. Gloyne, S. R . 1933. T he m orbid anatom y an d histology o f a sb esto sis T u bercle 14:550-558. 5. W ood, W . B. & S. R . Gloyne. 1934. P ulm onary A sbestosis, a review o f one hundred ca se s L ancet 2:1383-1385. 6. Stone, J . J . 1940. C linical stu d ies in asbestosis. A m . Rev. T uber. 4 1 :1 2 -2 1 . 7. SEUKOFF, I. J ., J . CHI RG & E . C. Hammond. 1964. A sbestos exposure and neoplasia. J . A m . M ed. Assoc. 188:22-26.