Document jBj2D7mJBpMJ0omeKaR49pGky

GeorgiaFfecific ^ ?ntracompany memo to K. L. Gipson; from T. E. Withycombe subject Occupational Cancer location location date PLAINTIFFS EXHIBIT GP-256 Portia id Portland September 1, 1976 Ken, enclosed is article by the director of the Mt. Sinai School of Medicine,Environmental Health Sciences Center,which is one of the articles cited in a recent petition to the Consumer Product Safety Com mission to ban joint compounds containing asbestos. I believe you will find the article interesting and particularly the reference to sinus tumors on Page 3, footnote 17. You may wish to review the article cited. fc Enclosure cc w/enc. : Mr. F. G. Breuer T. E. W. W0J Kecent Perspectives in Occupational Cancer BY IRVING J SELIKOFF In recent years, many previously unsuspected carcinogenic agents have been identified and new perspectives established for the evaluation of the increasing numbers of chemical substances introduced into the environment. i Attention is sometimes called to the fact that the first neoplasms for which etiological factors could be established, were occupational cancers. The report 200 years ago by Percivall Pott of cancer of the scrotum in individuals who had been employed as chimneysweeps (1), or that of chemical car cinogenesis in humans first described 80 years ago as "aniline cancer" (2), or that radiation-induced cancer had an occu pational starting point among miners in Schnccburg and Joachimslal almost 90 years ago (3), are cited. These claims are true, yet it is equally true that each was an isolated de scriptive observation, of muffled impact in its time. Accelerated development of a connecting mature body of knowledge, the discipline of occupational cancer,, _has__rathcx been a matter ofjhc past, lwo decades.,Although it was related to what went be Tore by the continuing productive studies of the effects of carcinogenic aromatic amines (2), if one event can he said to l>e the origin of this new phase, it may he the brilliant description in 1955 by Richard Doll of the association between occtipational exposure to asbestos and an important risk or death of lung cancer (4). Doll's demonstration of the applicability of chronic disease epidemiology provided an important example for future research. Many of the concepts we now take for granted in the evaluation of occupational carcinogenicity, as, the need for long periods of observation (5), the utility of cohort studies (6), the possibility of co existence of cancer and other biological toxicity (7). were in herent in his classic report. Similar approaches have guided the best of experimental studies and have increased their relevance * - ........ <:..... - /u\ With this background, a good deal has been learned about occupational cancer in recent years. This has included identi fication of carcinogenic agents previously unsuspected of such effects and the establishment of a number of perspectives which are now available for the evaluation of other materials used in industry and/or agriculture or which may be intro duced in the future (9). The latter achievement is perhaps more important, since the number and complexity of new or re cently introduced agents has attracted much attention, and little is known concerning their carcinogenic potential. LATENT PERIOD The above term is perhaps inexact since we do not actually know what is happening in tissues between the time of first exposure and initial evidence of clinical disease. Changes may be under way, albeit not detectable with current techniques. Perhaps "period of clinical latency" or "lapsed period" would be more exact (10). In any case, each of these terms describes an important phenomenon--that a considerable time must usually elapse between onset of exposure to an occupational carcinogen and the first evidence of resulting cancer. General ly, this period is 20--35 years, although as little as 10 -- 15 years may suffice, or 35--50 or more years will pass The lime sequence can be affected by a number of variables touched on IkIow, but it is remarkable how their influences operate with in relatively narrow constraints. Understanding this, two conclusions become evident First, it would have been difficult or impossible to establish the carcinogenicity of substances widely introduced only in the ViasKTx oji.i.ilc popui.i;..'!. m.......... ............ the expected background rates arc increased. Sometimes, espe occupational cancer in the burgeoning petrochemical industry cially if less common tumors arc being:conxidcrcd. as brain or and reliable evidence that this was occurring with any fre adrenal or kidney or lymphoma, extensive observations are quency- In considerable part, the contradiction remains. On necessary, if not of moderate sired groups over long periods the one hand, the industry deals with a very large numlver of of time "(after the 20 year point!), then of very large groups chemicals which either have been shown to have carcinogenic *or shorter periods (to achieve an adequate number of "person- potential in laboratory animals, or arc related to these chemi years'* of observation). cals., belonging to such suspect groups as the polycyclic aroma In a number of instances, unusual tumors have been ob tic hydrocarbons or some of the halogcnatcd hydrocarbons: in served in considerable numbers for which the usual c.xpcctcd- several instances, as benzpyrene or /7-naphlhylaminc. occupa observed ratios arc almost superfluous. When cancer of the tional cancers in humans have been clearly established. On the scrotum occurred among Pott's chimney sweeps the absence of other hand, the number of chemical agents so incriminated has biostntistical calculations did not prevent recognition of the remained comparatively small and the number of workers unusual situation. Sinus tumors among woodworkers may be involved, limited. looked aUn somcvvhat the same light (I fjT With the recent identification of vinyl chloride induced Two "neoplasms, infrequent in general hut common with cancer (27. 28). the situation has changed somewhat. It is industrial exposure, have demonstrated that such "signal*' still not known whether a good many of the petrochemical tumors can he important factors in identifying occupational industry's materials will turn out to be carcinogenic--in large carcinogenesis. One. hemangiosarcoma of the liver, has as part, an adequate "latent period" has yet to run its course, sumed such a role recently and will be discussed below. The to allow for proper evaluation. Still, to find that a key chemi second, mesothelioma, has a longer history. First reported in cal in the giant plastic industry was clearly carcinogenic has the pleural cavity of an asbestos worker in 1953 (IS) and in the been disconcerting. Further, it was sobering to realize that if peritoneum of another the next year (19), its link to asbestos vinyl chloride's carcinogenicity had been expressed in increased was firmly established in 1960 (20) whem in a series of 47, risk of cancer of lung or colon, elevated rates of neoplasms of eases'in one laboratory in* South ATrica. over a five year these sites among the affected workers might not have been period. 45 were shown to have had opportunity for asbestos identified for some years, at the earliest. Tbc_fact_that it was exposure of one or another, type., decades before. The impact an unusual tumor, hemangiosarcoma of the liver, otherwise of this finding can be gauged by appreciation that, in general, rare in the general population (perhaps one in 10000--40000 approximately one in a thousand deaths in the general popu deaths), which occurred, attracted attention. lation had been known to be caused by these previously un Three cases in one plant, the B F Goodrich Company in common tumors. With occupational asbestos exposure, these Louisville, Kentucky, were sufficent to establish a strong sus tumors have proven common (21). In some cohorts of asbestos picion of the risk (29) and the suspicion became a virtual workers, approximately five or six percent of deaths have been certainty when the same neoplasm w'as found in other vinyl- due to pleural and peritoneal mesothelioma (5). In others, chloride polymerization plants, making vinyl chloride the the percentage is lower; it has been reported, for example, likely offender, rather than other coexisting chemicals, as that this neoplasm is less frequent among Quebec chrysotile special additives or process chemicals, peculiar to the Louisville asbestos miners (22). When found in family contacts, it led plant's operation. At the same time, the fact that only a dozen to the understanding of the danger of bringing dust from and a half cases came to notice in the first five months after the factory to the home (23), when found amid residents discovery of the condition did little to allay concern, since in the neighborhoods about asbestos plants, it bespoke un these cases, when analyzed, had begun work, on the average, controlled asbestos air pollution in the past. In South Africa's approximately 20 years before death, at a time when the large series of eases, with adequate history, only approximately vinyl chloride-polyvinyl chloride industry was limited in size fifteen percent have been judged not to have had some known and still employed relatively few workers. Of the 19 cases asbestos contact (24). Thus, vchcreyer_mcsqtheji<iaxa_is..toyn d recorded by mid-June, 1974, 15 had begun work 1944--1952, asbestos is sought. In this way. otherwise unsuspected oc with an overall average of 20.4 years from onset for the group cupational exposures to asbestos have been identified--in ship as a whole. Since the great majority of workers in vinyl chlo yards, especially (25). ride-polyvinyl chloride plants were first employed during the 1950s and 1960s, it was evident that the full impact of vinyl chloride tumors would not be known for another two decades. ENVIRONMENTAL CANCERS FROM OCCUPATIONAL * Limited data so far available suggests that, at least for poly SOURCES vinylchloride polymerization workers, the incidence of oc An important dimension was added to occupational cancer with the discovery that neoplasms might occur with the dis semination of the agent beyond the factory gate, either by its release during the manufacturing process or from resulting waste, or by contamination of households with the offending material being brought heme on workers' clothes. Although instances of such disease had been known before (20), the full import of the problem was not appreciated until Newhouse's report in 1965 (23) when she demonstrated that, of 76 con firmed cases of mesothelioma in the files of the London Hos pital, of the 45 not .known .to. have had occupational.exposure tojisbestos, nine had simpIy.Jivcd in the households.oLasbestos workers ("conjugal disease") and 11 had neither worked with the material nor lived with someone who had been so em ployed, but had resided, many years before, within one half mile of an asbestos'"plant in London. This finding was soon confirmed (26), and the principle of carcinogenic risk derived cupational cancer will he significant. We have examined the mortality experience of a cohort of workers employed at a large polyvinylchloride polymerization facility in the United States. The plant opened in 1946 and from that year to 1963. 257 individuals were employed in the production process for five years or more. While exposures began in 1946, relatively few individuals were employed prior to 1951, when a significant increase in the work force took place. Thus, the majority of the cohort has had a bare 20 years or less from onset of exposure. An initial report of the experience of these men has been made (30). We have traced each of the 257 individuals to December 31, 1973. Twenty-five were found to have died, of all causes. Three of. the_doalhs, each confirmed at autopsy, were due to hcmangios'arcoma of the .liver (Table 4). Ages at death were 41, 54, 60. Elapsed time from onset of first expo sure to death was 14, 17, 23 years. from occupational sources is an important factor in current evaluation of control of environmental cancer, whether it be DOSE-DISEASE RESPONSE RELATIONSHIPS from radiation-producing power sources, agricultural use of Discussion of this thorny question, with social, ethical and pesticides, air and water pollution from petrochemical industry economic implications co-minglcd with scientific perspectives, operations, carcinogenic mineral dust, or other suhstanccs or was stimulated and made much more acute in the evaluation processes (II). These considerations arc separate from those of regulatory measures necessary for the control of vinyl involving cancer risk with end-product use, either during chloride cancer. While it has been generally agreed that the further industrial manipulation of materials or in utilization risk of malignancy increases with intensity and duration of of consumer products. exposure, there has been much less concordance in the evulu- nol Ik able, with pic\t.vii k ni^luigc, to identify cancer n.'.k m nancy, .mu since .u icas. senne miiMiii; e in ns i.. >....... . luunans of recently itimKlucctl agents for another two oc cveo_ to Income more complex, this may turn out to Ik of consider- three decades.(I I). and epidemiology must look to assistance able practical importance in the future. front other disciplines. Parenthetically, a similarly long period Second, animal studies generally arc directed to the investi must elapse before it can, Itc ascertained whether measures gation of one agent; negative results may therefore Ik mis dcsfgncd to correct an occupational cancer hazard arc actually leading insofar as actual work risk is concerned. (To com cctivc. This has been Jhc ease, for example, among nickcj pensate, one should hasten to add. dosages can Ik far greater ^richer workers (12). than those which occur in industry, and carcinogenicity en "I he importance of the principle of clinical latency has per hanced). haps nowhere been belter demonstrated than with lung cancer associated with occupational exposure to asbestos. In cur SIGNAL CANCERS Laboratory, we have been following a cohort of aslKstos in Most occupational cancers are identified as occurring as in sulation workers, composed of all 17 800 members of the creased nunitKrs of common malignancies. Thus, increased Union of such workers in the United States and Canada on rates (taking age, year and sex into account) of lung cancer January I, 1967 (5). By December 31, 1972, 1356 of these men occur, for example, with occupational exposure to. tale, chro had died, almost 400 more than had been expected. There mates, arsenic, nickel carbonyl, uranium mining; fluorspar were 115..dcaths_of -lung cancer, whereas only 56 had been mining, hematite, /5-chlormcthylclher and asbestos; of blad- anticipated. Analysis c>f the work history of these men indi cated that the excess deaths _wcrc_.largely limited in those _wprkers_whp .had achieved morc_thari.20 years from onsct of ^ ~theirwork (Jahics. I. a nd_2). _ " The risk of lung cancer with occupational exposure to asbestos could easily he missed, and inaccurate conclusions drawn, if studies are made without the opportunity to ob Tablt 1. Expected and observed dealha among 17 800 asbestos Insula serve a sufficient number of individuals 20--30 or more years tion workers In the United States and Canada January 1, 1967--Decem from onset of work exposure. Similar results hate been ob ber 31, 1972. tained in studies of uranium miners (13) and workers in nickel refineries (14) and with other agents; indeed, when many lung Duration from onttl of exposure cancers arc seen after significantly shorter periods, as with Less than 30 years More than 30 years ^-chlormethylcther (15), one might justifiably suspect rather Expected* Observed Expected* Observed intense exposure or particularly virulent agents. Total deaths--ali causes 303.90 249 756.12 1109 MULTIPLE FACTOR ETIOLOGY Investigations of occupational exposures for carcinogenicity Cancer alt sites Lung cancer Asbestosis All other causes 30.43 S.40 173.46 64 146.13 28 47.47 7 178 610.99 511 347 $4 504 generally seek to isolate the suspect materials. This is reason Number ol persons 12 681 5119 able. Nevertheless, this approach is in a sense artificial, since carcinogenic agents are infrequently used singly, but rather in implex work environments, often with a variety of other bstances of unstudied potential, and by individuals whose personal and social environments are equally varied. The Expected rates are based upon age-specific white male death rate data of tne US National Otlice ol Vital Statistics. Rates lor 1973 were extra polated Irom rates Irom 1967--1971. US rates are not available, but thesa are rare causes of death in the general population. - possibility of interaction of two or more agents has long been known in the experimental setting; since 1968 it has been shown for occupational cancer in humans as well (16). Jt was Table 2. Deaths from tung cancer among 17 600 asbestos Insufallon found among asbestos workers, for example, that lung cancer workers in the L*C and Canada, January 1, 1967--December 31, 1972; risk was not significantly increased jmong those men who did relation to elapsed period Irom onset ol work exposure. not also have a history of cigarette smoking. Those,who did, "had much more lung" cancer ihan'c ig are (IF smoke r?. in general^ Lung cancer "Asbestos exposure thus markedly increased the lung cancer risk of cigarette smoking: it has been calculated that an Years from onset Expected deaths* Observed deaths Ratio asbestos worker who smokes cigarettes has 92 times the risk of death of lung cancer compared with an individual of the same age who neither smokes nor works with asbestos (16). The powerful multiplying effect of the combination of two agents can be appreciated by examining the experience of asbestos insulation workers cited above. When the cohort was established, the smoking habits of the majority of the workers was recorded; 9590 had a history of cigarette smoking. 609 had a history of pipe and/or cigar smoking but no cigarette smok <10 10-14 15--19 20--34 25--79 30--34 35-39 40--44 45--49 50 + Total 0.66 1.97 6.87 9.55 10.70 6.30 4.68 4.84 4.51 4 97 55 67 0 mmm 5 3.5 23 3.9 34 36 56 S3 60 ,, 7.3 39 6.2 27 56 19 4.3 33 4 4 275 4.9 ing, and 1457 had never smoked at all. Their mortality experience, with particular reference to lung cancer, is detailed in Table 3. Anionc those who never smoked, only Expected deaths are based upon age-specilic white male death rate data' of the US National Olhce ol Vital Statistics. Rates lor 1973 were extra polated from data from IS67--1971. one lung cancer was seen from January I. 1967 through De cember j l, iv72. The pipc.andjrigatjmokinfi_roup,,.a.lsQjiatL. only bnc~lujg.pq.nccr dcajp. On the other hand, there were 179* lung cancer deaths among those with a history of cigarette smoking, although only 32 such deaths were expected to occur.' This, despite the fact that all of these men had worked in the Table 3. Expected end observed deaths ol lung cancer among 17 800 US and Canada asbestos Insulation workers, January 1, 1967--Decem ber 31, 1972; relation ol cigarette smoking. ime trade, with equal opportunity for occupational exposure ,o asbestos. The significance of the principle of multiple factor inter No of Deaths tiom lung cancer persons Expected* Observed fletio action has many ramifications. Two arc of immediate interest. First, sonic substances, by themselves, niav have no careinop,emc effect; in concert with others, malignancy m.iv occur, '{inch influence may lie additive or muJtiplicalhc (theoretically, Smoking habits nol known History ol cigarette smoking -No history ol cigarette smoking Nover smoked History ol pipe and or cigar only 6144 9590 7066 1457 603 16 76 31 60 7.51 4 40 3.11 4 56 17 57 3 03 1 03 1 03 there could also he a protective effect, as well). As a corollary, substances now deemed innocuous may change their hahil in new circumstances; our vigilance must Ik constant. Too. since ** '. f it.i .............. Expected deaths basod upon aga-specilic US mortality cates tor white males disregarding smoking Lung cancer estimates basod upon US tatos *->r cancor of lung, pleura, bronchus and huchoa. calegonos IS? and If) of the International Classification ol Discosos and Causes of Doatns. tot ; et fticti yeiti- Cancer* el all tile* -- . - -- i. Ilomanpiosarcoma o( liver i Neoplasms ct lymphatic end hemalopelelic tissue* Brain (Glioblastoma) ' *>CI*I>* ion __________ Bone Cirrhosis (with esophageal vric*s) Post-operative bleeding (Chololilhiasl* Cardiovascular dl*e***, ether______ * i ,i -1 i. _______________ ________________ 1 ation of whether a lower threshold existed below which cancer would not occur. There have been few data bearing directly on this aspect of the question and, in the nature of things, it might be that such data are unlikely to appear. `Negative" experi ments, to be convincing, would have to involve very large numbers of animals and, more important, observation of very large numbers of vinyl chloride workers exposed for pro longed periods of time at measured low levels of exposure to the monomer. Even if these data should be obtained, they would always be only an approximation, since further study conceivably could show exceptions. Theoretical considerations would seem to indicate that there is no identifiable lower, threshold limit for carcinogenic agents (31). The proposed regulations for the control of occupational exposure to vinyl chloride in the United States seem to approach the problem f,om this point of view; a level of one part per million has en proposed (32) which, interpreted in practical terms, ..ight be considered a `no threshold" level but one, which allows for inevitable mistakes and accidents which might occur in the industrial environment, as well as recognition cf practical problems concerned with instrumental monitoring of the work environment PRETESTING OF NEW MATERIALS Recognition of the long period of clinical latency between onset of exposure to materials in the occupational environment and their carcinogenic effect, if this is to occur, has recently raised the corollary question whether we_might anticipate such evaluation and_sIiorteit-OE-.eliminatc,-thi& periodjDf-uncertain1y. Much attention is now being paid to this possibility. Until recently, however, expectation and desire exceeded promise. Although structural similarity to known carcinogens might occasion a high level of suspicion, cancer potential does not necessarily follow structural resemblance: many exceptions are known. Further, while suspicion could be directed to agents with biological activity other than cancer, many are known with toxic effects on kidney, liver, lung, central nervous sys tem, without concomitant recognized cancer potential. Experiences with vinyl chloride and /}-chlormclhylcthcr suggests, however, that laboratory scrccping.might.be feasible, for at least some agents. In each instance, laboratory studies were able to establish the carcinogenicity of a chemical sub stance which was later shown to he carcinogenic in man (28, 33). It is not known whether such experimental screening ap proaches will be equally productive with other agents, nor hctlicr other laboratory techniques, including mutagenic Indies, will extend their utility (3t). Certainly, this is to be hoped for and much work, is being initiated to provide infor mation on the question. Guidelines that would point priorities for selection of agents to Ik tested arc also heing discussed, and include such considerations as chemical structure, evidence of other biological activity, number of workers likely to Ik exposed. For substances already in use. similar considerations could apply, with the added dimension that epidemiological studies should he suggested when there are available groups of - lings, l/uidon, I775)pp63 - 68. 1. J C Areas *nd M F Aip*. Chemical induetitm of Confer (Academic Press. New York. l974)Vollinpp)-4. ). A Pirctun *nd It Sikl, American Journal of Cancer H, Ml (19.12). 4. R Doll, British Journal of Industrial Medicine 12, It (1933). 5. IS Scliltoff, E C llammond and It Sridman. in Biological Effects of Asbestos. P Bogovski, J C Gilson, V Timbrcll and J C Wagner, Eds (International Agency Re search on Cancer. Lyon. 1973) pp 209--did. 6. T F Mancuso and E J Coulter. Archives of Environmental Health 6 (2). 210 (1963). 7. i J ScItkofT, 3 Churg and E C Hammond, Journalofthe American MedicalAssocialion 118. 22 (1964). I. J C Wagner, G Berry, 3 W Skidmore and V Timbrel!. British JournalofCancer 29, 232(1974). 9. E C Hammond and I 3 Selikoff. in Analytic and Experimental Epidemiology of Cancer. W Nakahara.T Hirayama. K Nishioka and It Sugano. Eds (University of Tokyo Press, Japan, 1973) pp 41--49. 10. I J Selikoff and E C llammond. Environmental Research 4 (2) ii--Hi (1979). II. 13 Selikoff and E C llammond. Proceedings of the 7th Rational Cancer Confer ence, Los Angeles, M7 (1973). 12. R Doll, L G Morgan and F E Speizer, British Journal of Cancer XXIV (4), 623 (970). 13. F E Lundin, Jr. 3 W Lloyd, E M Smith, V E Archer and D A Holaday, Health Physics M. 371 (1969). 14 E Pedersen, A Hogetveit and A Andersen, International Journal of Cancer 12. 32 (1973). 13. W G Figueroa, R Raskowski and W Weiss, New England Journal of Medicine 2*8 (21). 1096(1973). 16. I J SelikofT, E C Hammond and J Churg. Journal of the American Medical As sociation 204(2). I06(I9M). 17. E D Achtion-AJLCowdrll and E R*ng, BritishJournal oflndusirialM<fliC.iat.2i___ I*. A Weiss, Medirinische3,83 (1954). 19. F Leichcr, Archivfiir Cewerpathologic und Ccwerbehygiene 13.382 (1934). 20. J C Wagner, C A Slcggs and P Marchand, British Journal ofIndustrial Medicine 17.260(1960). 21. J B Enticknapand WJ Smither,ibid21.20(1964). 22. J C McDonald, A McDonald, G W Gibbs. J Siemialycki and C E Rossiter, Ar chives ofEnvironmental Health 22.677 (1971) 23. M L Newhouse and H Thompson. British Journal ofIndustrial Medicine 22, 261 (1965). 24. 1 Webster, South African Medical Journal 47 (5). 163 (I97J). 25. P G Harries, Annals of Occupational Hygiene II. 135 (1968). 26. J Licbcn and H Pisiawka, Archives of Environmental Health 14, 559 (1967). 27. PL Viola. A Bigoltiand ACaputo. Comer Research 31.516(1971). 28. C Maltoni and G Lefemine, Environmental Research 7. 381 (1974). 29. J L Creech and M N Johnson, Journal of Occupational Medicine 16, 150(1974). 30. W J Nicholson, H Seidman, E C Hammond and IJ Selikoff, Annals ofNew Fork Academy ofSciences, in press. 31. Evaluation of environmental carcinogens. Report to the Surgeon General. USPHS, April 22,1970, Ad Hoc Committee on the Evaluation of Low Levels of En vironmental Chemical Carcinogens. 32. US Department of Labor Occupational Safety and Health Administration. Expo sure to vinyl chloride: occupational safely and health standards (Federal Register 39:35890-35898. October 4.1974). 33. B L Van Duuren, B M Goldschmidt, C Katz. L Langscth. C Mercado and A Sivak, Archives ofEnvironmental Health 16,472(1968). 34. U Rannug, A Johansson. C Ramel, C A Wachtmeister Ambio 3. 194 (1974). 35. Research supported by grant ES 00928 of the National Institute of Environmental Health Sciences and by the Environmental Cancer Research Project of the Ameri can Cancer Society R-53 B. Dr Sellkott serves Prolessor ol Community_Mediclne al Jhc Mount Sinai School ol Medicine ol the City University ol. Nevg jfork; and _a* Dirccloc--of -JU-. Environmental Health Science) .Center. A past President of the New York Academy ol Sciences, his Interests now emphasize problems ol environmental cancer, particularly those associated with materials In Industry. How ever, his research has In the past also Included other diseases; and lor many, hi* achievements In environmental disease re search are matched by his contributions In the introduction of Isonlazld lor the chemotherapy of tuberculosis, lor which lie was honored by the Lasker Award of the American Public Health Association In 19SS. His address: Mount Sinai School of Medi cine, Filth Avo and 100 Slroct, New York, N Y 10029, USA. r