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FILE NAME: Shipbuilders Council of America (SHIP) DATE: 1973 Nov DOC#: SHIP051 DOCUMENT DESCRIPTION: Journal Article - Recent Developments Industrial Carcinogens Review Article Recent Developments /> --t in Industrial Carcinogens oo cnU 3 Robert f . Eckardt M .D., Ml D. tn T h t topic of ca/cmogens it one about which then it much confusion and alio much misunderstanding. `Thii in turn leadt to the development of lean and apprehensions. At tn clinical medicine, the word cancer in industry immediately tcem i to lead to despair, whereat our approach thouid be straight forward and intelligent. I think of cancer in industry ju it at I do about any other potentially toxic problem in in* dutiry. What we need when a problem develops is knowledge--knowledge ol the process knowledge of the chemistry, knowledge of the exposure The mote w e know the more likely we are to arrive at satisfactory solution*. In this respect, then, cancer in industry is kite any other problem solving. fin e we have to have some knowledge of the experimental methods used by oncologists to test for carcinogenicity. In the case of the skin, the tests are relatively straightforward. You w ill note that I say "relatively" because Jn fact even a skin car cinogenesis test has many elements that may serve to com plicate it Thus w e know that mice, hamsters, and rabbits do develop skin cancers in response to chemical agents painted on the skin white rats and guinea pigs seem to be refractory, and monkeys are resistant, taking long periods to do so. Thus the mouse hat generally become the animal species used in this type of experiment Painting is usually done three times a week. If done more frequently the material applied may so severely damage the skin as to make TterpreUlion of results difficult If done less frequently the latent period for cancer development may be so long tint the animals die before developing cancer. Painting should be done with a minimum of rubbing to avoid damaging the skin. Some workers even use a miCTooipttto so that no nibbing at all is done, just letting the material spread over die shaved skin in an accurately measured dose at each application The animals should be weighed periodically because if the material being painrad is tone it may interfere w ith their growth and we know that this in turn wiH interfere with tumor development cause a skin-painbng experiment rakes so long--up to iw o years--people are always looking for shortcuts They want a chemical test or an accelerated biological test that w ill give them an answer in a few days or a few weeks. However desirable this may be, to tar none of them have held up when examined closely. Thus it was found (h it some carcinogens would cause atrophy of the sebaceous glands of the skin and tint was once proposed as a 'quickie" test However, in a study of 130 compounds, Bock & Murid' found that some car cinogenic compounds did not cause sebaceous gland atrophy, w h ie some non-carcinogenic compounds did Some chemical Or (d m * O n cw . MeUerl am u c k Qmwn, t e e I w a x S end Catnpt*) lo r *S. lin d m Ml CTOIS 904 tests may have limited application, but because of the wide variety of chemical compounds that have been shewn to have carcinogenic activity it would be anticipated tlut no single chemical lest would have universal applicability. Suffice it to say that an expert panel convened to advise the food 4 Drug Administration concluded that there were no truly satisfactory short-term tests that had been sulficienilTprovtn that they could substitute for long-term carcinogenesis tests.* Some people hive recommended that the material to be tested simply be injected or implanted s- hcuianeously into rats or truce. This has the advantage of a known dose end minimal handling of the anim als.' But this method so Ui has been shown to produce malignant tumors (sarcomas) in response to cellophane. Dacron, polyethylene, polyvinyl chloride, silastic, Pliofilm, Nylon, pofymethyl methacrylate, polystyrene. Saren. Ivalun, ICet-r, lotion, silk,* and glass cover slips.' in our hinds, w e found that a complex oil shown to be carcinogenic to the skin when painted caused a local abscess when injected subcutaneously which subsequently sloughed cut without tumor formation Thus this route of testing may have limited application, especially if tumors are produced at a site distant from the site of injection, but if sarcomas at the site of injection are the only tumors formed, interpretation of their significance becomes extremely difficult Another suggested test is that of implanting the material in the bladder of mice. This suggestion arose. I believe, from an enbre misconception. Thus in die study of bladder tumors oc curring in workers in the dye industry, beu-naphthyUmme, when administered subcutaneously, was shown to produce bladder tumors in dogs but not m mice In searching for the reason for this discrepancy it was found that both man and dogs excrete 2-amino-1-naphthol as a metabolite of beta- naphthyiamme in their urine, whereas mice do not Dr. Ceotgianna Homer, In England, concluded that maybe betanaphthyiamme was not the carcinogen after ail but the metabolite 2-anuno-1-naphthol was. To test out this theory she Impregnated small wax pellets with 2-amino-1-naphihol and implanted them suigically into the bladders of mice. Sure ik enough, the mice developed bladder cancer. However, subsequently it has been shown that cholesterol, glass, stoanc acid, magnesium stearate, hexadccanol, octadecanot, and naphthaline* (the old-fashioned moth bail) all produced blad der tumors and cancers when implanted into the mouse blad der. None of these are suspected of bang carcinogenic. Thus this lest does not seem to be a very sound one. incidentally, these studies of the metabolism of beunaphthyUmme have ted to extensive metabolic studies and bnsk scientific arguments about what truly the carcinogenic agent. One school supports the 2-ammo-l-naphthol metabolite a- iK- <arr,r|.x;> i. wl>icu* i nolhi-f tK-hevm that hyrlruxylaiioii m itv n "<>'1 atom nr the ammo group (va-ratlcd S tv lri.m a tio rtl 1- ih.-rardrwgirn, while yU nthi-fy bHtt-vt-dll itrvnt art the true carcuv^i-n fh e v ilu d iei have h m i U'tinating Hum a biochemical standpoint and haw 't'.rO to k.-vp man) c iin * biochemist* hid ai watt; m the !lb',r*tia/% but probably do not hive much p ut lic it im plication lor mduitriai cin ert prevention However 'he studies <i the implantation o< choleylerol. yieatvc Kid. end other materials into the bladder, previously mentioned. itw> hive serious practical con- sideniiijm tor other studies Thus dietfwlerw ulvcol and other material, ire claimed by tame to be 1 carcinogen on the b in s thit they h ive produced blidder cancers in mice. However, such tumors and o ncers never developed unless (m l 1 ^ted der stone s s it produced. The question then irises--is the chem icii 1 carcinogen, or is the stone the carcinogen* It is in teresting to note that the first experiments with cyclamates were undertaken w ith such bladder implantation techniques and had to be discounted until (ceding experiments were com pleted Even now the eyetamale picture is m i clear because them is some question that the experimental animals may have been infected with bladder parasite*, it it w ell known that Bitharm . a bladder infestation of humans by Schistosoma fxmatobium. is asiociaied with bladder cancer. In Egypt, where Btlhaizi* is endemic, bladder cancer incidence is quite high- The Schistosomes enter the body through the flan horn water in which the Egyptians are walking in eating for thru fields from there they enter die bloodstream and ultimately end :ip m the bladder. Incidentally, the secondary reservoir for the Schistosoma hematobtum is the snail, and much work is going on trying to find an agent that w ill kill the snail without producing other undesirable ecological affects. The approach is like killing the mosquito to eliminate malaria. Another approach that lu s been recommended to try to shorten the necessary test period for carcinogens is the use of newborn or sery young (suckling) m ic e /ll was suggested thrl an increased incidence and earlier appearance of malignancies could be obtained trom 1 single injection of potent car cinogens However, newborn rats did not respond in the same way as newborn mice.* Rather, they responded like adult mice, further, more complete studies have shown that this lest method probably has few true advantages.* It may be that the use of newborn ot ,ery young mice was predicated on the ab sence of detoxifying enzymes m the newborn which sub. sequently appear as the animal ages. It is known that a benz pyrene hydroxylase exisis in the gastrointestinal tract," and it is further known that newborns are frequently lacking enzyme systems that are present in adults. Even today, however, there are those who strongly urge tht newborn as a test animal system. Turning to experimental lung carcinogenesis, it is now beginning to appear that multiple factors are probably necessary to produce lung cancers in experimental animals Thus in rats a combination of repeated influenza vuus in fections plus ozonized gasoline" or sulfur dioxide and benio!)pyr*ne" or 7,12-drmethyf-ben*(a)anthracene pluv india in k " or, in hamsters, hematite plus beruo{a)pymneMall have led to lung cancer production. The evidence indicates that pure poiyaromanc compounds Uke beruofa) pyrene are rapidly removed bom the lungs. However, when introduced with particles or with SOr which may impair the ciliary )etAil 0) Octupaiioui Ue*cim /fai IS, No. lJMovsmbst 1973 ST0095672 tem o .il nv-thaniwns, n-siili-ncc- time w iitvn trv lur^; may t*. m uih (Kuiiuiuftl, inti 1: is this incrt-avcxl rrvvh-nte tune w ln h the cxpruriiriitelivls believe loads ro the production <* lo^ cancer llu> experimental work on lung cancer is in its v..<> early stages. and U is Ion sixm yel to draw detinitive elusions on it One very interesting lung cancer eajjerimeni n iais wav nut conducted try laskio era/ " These worker* exposed rats to 0 1 (ffn Id tiwfi hl.aiim .ala.il .atyu >. hours per day. live days ftrfji' week hjt a tout of 101 exposures Nineteen cut of 30 rats so exposed developed squamous ceil cancers of the lung or can cers of (he nasal epithelium O f 1merest m tins conntcbon is that subsequently in * chemical plant in California where bnlcMoromethyl) elher was produced several cases of lung cancer were reported. 1have only teen newspaper-type repot* of these cancers in these chemical workers* so I am not able to comment intelligentJy further on them. If in fact this is so. ^ may represent the first lim e the detection of a carcinogen b^ Jaboratory tests has subsequently beeiOofTowcd by the aojx u rin c x ot cancers in human*. Usually eprdemiologKil studies hive shown the pmsence of cancers in human*, and thit in turn ha* led to an intenswt search in the laboratory far the carcinogen It is of interest that these workers have also been able to produce lung cancers In experimental immi* w ith 2.3-dtChloro-a-dioxane. ethyl bromoacetate, and tr i emchlorbsdnn.* although these are weak carcinogen*. T h e /fit demons'rauon of weak pulmonaiy carcinogenesis in ammais/t' >with these compound* should alert everyone to minimize human expo- are* to them and to follow worker* exposed to them with extra vigilance. fo r completeness it should be mentioned (hat pulmonary carcinogenesis in animal* has been demonstrated for betytbum." mckel carbonyl,1* and radioactive materials.'* In terestingly enough, inhalation pulmonaiy carcinogenesis has not yet been demonstrated in expenmenu! animal* lor chromates* or asbestos,* although the lo m has pcratmwl f n . tm l'fnfru lex when inn*rad fnt/im n^yHyrtf iWraglcuraHy. ' V 1 * , and the latter has produced pulmonary fibrosis (avbestosis) when administered by inhalation* and malignancy when given intrapteurallyMin animal*, fin ally, various epoxide*, lac tones. and peroxy compound* have been shown to have a car cinogenic potential.** With this far-from-complete review of experimental car cinogenesis which has been given only to emphasize ihe com plexity of the problem, I should now (ike to turn to some in teresting recent epidemiological work. I shall not try to cover skin cancers in coal tar workers, mule spinners, cutting oil user*, wax pressmen, and the like, lung cancers m chromate workers, nickel refining, or asbestos w a ken (other than in sulators), bladder cancers in (he dye industry, nasal cancers in nickel refining and isopropyl alcohol manufacture, or bone sar comas in radium dial painters because these have been covered in my book* or other works. Presumably we arc discussing recent developments. Much publicity has been given recently to asbestos as a pulmonary carcinogen and producer of pleural or peritoneal mesothelioma. Actually pulmonary cancer in asbestos workers has been recognized for 25 to 30 y e a rs* The condition was catapulted into prominence by the observations of Wagner^ in South Africa among miners and processors of asbestos and especially by Sehkoff and his coworfcers* among tmuiaiton workers What has made Sehkoff and tvs associates' work 90S ST0095673 iiauum I his b- - i iht-ii uv- lit union rrt rink l( study this m n d'i'on n*-irftjv m\uljtrws usually don't svurk lot OCX' single 'mnlrui'i hot rj'h tt most- (i<tm |ob to |nb wherever work is available and thus work tot mult.ptr employers, it was VCty rliitirutt to nbljm any kind ri picture ol svhal then health ex penwue k<t hrrn except through union records When these w rte t-xam-ned it was found that of 612 workers who entered th trde bc-iore t941 and were traced through 1962. 45 had died m earner of the lung or pleura Only 6 to 7 men would hate boon cpected to die o( lung or pleural cancer if the nor mal incidence had prevailed Another interesting observation has W n thattt* incidence of lung cancer among asbestos in sulation workers who smoke cigaiette* is lar greater than for those who do not smoke." It ts to be hoped that the industrial hygiene measures introduced among these workers wilt soon have this situation under control.* There is still some dispute among workers m this field of whether the asbestos h a direct carcinogen or whether its carcinogenicity is due to certain oils that may he piew-nt m Use asbestos naturally or through Con tamination." " Of perhaps more concern has been the ob servation that asbestos bodies can be found in the lungs of a very high percentage of people who come to autopsy and have never been exposed to asbestos its their work.*1Although this is of concern to many people, no one is yet prepared to say what its significance is. It is important not to jump to as-yct unwarranted conclusions on this observation, as I have often heard Dr. Setikoff say in talks on the subject. As many people suspected, lung cancer incidence among uranium miners has been shown to be increased." Again, (he nsk seems to be much higher among smoking miners than among nonsmoking miners There have been 62 tung cancer deaths among 3,414 white miners and two among 761 non white miners Them seems to have been established a dosetespome mtaiumship which may hooefulty permit the elimination of this disease in the fuhitr Recently an outbreak o* bladder cancers occurred among workers in the electric cable industry." This apparently resulted from the former use of beta-ruphthyfamine as an an tioxidant m the tubber sheathing used on the cables. Since this material has not been used by the rubber industry as an an tioxidant since about 1945, it it anticipated that these tumors w ilt soon disappear However, it does point out the long latent period that can occur, and that in searching for etrologic agents m occupational cancer it may be important historically to go lar back into the processes lo find the responsible agent Among 8.047 workers in a metal smeller works, 147 res piratory cancer deaths among 1,877 total deaths were repott ed * The causat.se agent in this case was believed to be ar senic inertide exposures by inhalation, although some relation ship to 5 0 i exposures was also demonstrated This recalls the association between sulfur dioxide and beozo(a)pyrene in animals demonstrated by the NYU gro*ip and previously discuss'd " A_ real surgrise has been the dempnst.-a'.or. in England'1 of an increased risk of nasal cancer occurring in woodworkers in the lumiture industry This seems to be associated w ith the use of hint woods To date, no one has come forward w ith a good t u n . i . to what the causative agent might be in this situation Ur-n-xihv-rlly. this observation w ill lead to extensive laboratory stud-ex. both chem ical and biological, m an attempt to un cover !* causative agent ' he accumuiat.on m the literature of cases of leukemia following biTtrtfV pxprisutns1***1 leads to the inevitable con clusion that benn-ne is a k-ukemugenic agent, particularly in cases that have previously displayed a panmyelopathy * Although ttys had long been suspected, the data tepormd in the literature was nut sufficiently convincing to establish the Inikemogenk nature of Iinverse. However, the more recent observations seem lo establish this association beyond a doubt More recent observations of chromosome changes in workers exposed to benzene* * lend further weight to the leukemogenk nature of benzene, tn any event in our own operations we are proceeding as if benzene was a leuken.ngrnic agent eliminating exposures wherever possible and reducing them to the lowest passible level where com plete elimination cannot be accomplished It has been teptarted4' * that lung cancer incidence in (Vaat- . ^ 7f spar miners is 29 times the expected rue It was found in this situation that radon and radon daughter exposures are in ex cess of the maximum permissible concentrations and k is believed that this is the cause. In this respect these lung can cers are similar to those seen In uianlum miners and in the okf loachimsthil-Schneebuig mines. A study ol tung cancer among coke oven workers in the steel industry* showed that they suffered a 2-1/2 times increated Incidence of that disease. This increased to five times among men who worked topside on the ovens, and to ten times if they worked five or more yean fulltime topside. If is likely that exposure to very high levels of benzo-a-pyrene and similar polycyclic aromatic compounds occurred, although H is quite possible, due lo the compter chemical nature of coal lar, that other promoting or co-carcioogenic, such as phenols or nitrogenous, compounds have contributed to the increased in cidence- Undoubtedly, intensive chemical and biological studies ol this situation w ilt be undertaken which w ill in time elucidate the causative agents and their comparative significance. t have tried to develop for you tonight some of the mote recent developments in experimental carci nogenesis as applied to industrial problem, and some recent epidemlofogical studies of industrial cancers. I believe our approaches to oc cupationally induced cancer should not differ from the ap proaches we use In any potential occupatiorsal toxicity problem. We should study and become intimately acquainted with the processes involved, not simply by studying engineering or flow diagrams, but by actually getting out into the work place end observing just what is done. This w ill give us some idee of the personal hygiene of the workers involved as well as possible industrial hygiene measures that may be ap plicable. We should conduct appropriately designed toxicologicil tests, in this case carcinogenic tests, un derstanding fully the limitations and pitfalls of any such tests we conduct. We should carefully examine the workers in volved to detect early signs of exposure or early pre-cancerout changes. Thus appropriate urine or blood analyses lor nickel or chromium, or for phenols in the case of benrene exposures should be matte, in some cases early biopsy or Papanicolaou smears of appropriate secretions should be undertaken At every opportunity, we should stress the avoidance of un necessary exposure t can think of no area where the '"operative efforts of industrial hygienists, industrial nurses and industrial physicians can have a moie salutary effect than in the control of industrial carcinogens and thus in the conttol of occupational cancels Recent Developments in Industrial Carcisnrr'sfTelurdl R eferen ces t t l . . t It. ....I V , ,J ,, ,, .K (.a ,n t**1sv tt-v ti.'/l #f* mrty**- u-fu. ..out ilarvk Cam w Art I f fill/. (Hill 2 fin d a H Ding Arlmm.i.tiaiiun VKitory f ummittte on Protocols <- V*-<A ( . 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Use oI newborn and infant animiK m car-, cinogwtn letting food Cm met Toaicof 0 14J, 1940. 9 fo>h B. and Shubik P Tone effects of 7,12-dimethyl berutafan- thracene in newborn and adult Swiss mice Nature 311428, 1946 10 Wallenberg tW er i t benzpyrene MvdrotyUre activity the gattrnmtestmai tract Cancer Ret 221120, 1962 I I Witety DV er af. The combined effect of repeated vital infection and espnsu* to cartmooewe aerosols on pulmonary tumor induction tn 0 7 black m t Amer A lloc, for Ctnctr Ret Pioc 137*. 1961 12 hutchnrr M. and U tkin S Combined efftett of atmospheric pollution 10th Intematiortal Cancer Conference, Houston. Texas. May 19?0 11 Shabad is ' Enperimental cancer of the king I War Cancer Imt 28 1T0>. 1961 U Safhotti U etaf Intratficheal iraectron ol panicuUtt carcmogem mto hamtier lung] Amer Attoc Cancer Ret Pros 4S9. 1961 13 latkm S. er 4f Turnon f the renpritory n e t induced by inhalation or BisicNoromethyt) ether Arch fFnvmn MefAh 21:115. 1971 16 Inttitule of (nvironmental Mccbcmr. Retearch tn Environmental Health Science! frghrh Annual Reportof Progrett USPHS Ceoter Granr ES 00260. Oecember }1, 1971. p 6* t7 Voniritd A), Reeves A l. and Urban ECI Evperimenttl Beryllium TotiCnfogv in H I Stokinger {Ed ). Beryffrum - fit Induttnil Hygiene Aspects Monograph of the Amer fndutt Hyg Attoc. and U S Atomic Energy Commotion. Chapter 7. pp 201-214. New York. Academic Pret* 1%6 in 5underman fW . and Oonnetty a i ASetattttiimi pulmonary tumnrt m ran induced by the inhalation of nickel carbonyl. 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I95S V Wagner 1C. 5Hgg> CA and hAarchand T O -'u'e pfeunf mesoihi-linini and asbestos exposure tn the North *Aes<etn Cape Province. for / Ind Med 17 260, I960 2B Selikofl II. Chuig I. and Hammond EC Asbestos esp>isui and nenplisti (AMA 1M 22. 1964 29 Sehkoft tl n al Asbettm esponuie. smoking, and neoplasia (AWA 204 106. 196B 10 Selikolf II. Pingram Duertn mufatron ffygieo* Prog-mi Reporn horn the ImuUhon Induttrf Hygiene Retearch Program 51 Hanrtgton fS Occurrence of bIH conuiwitg 1.4-benepyrene and leiated substances in atbette*. Nahrre 1914), 1963 12. Roe fC a af Tumour inibaiion by natural and contaminating asbestos o k Inmmt I Cancer 1491. 1966. 33 Sehkaff II. and Hammond EC tnvlronmeruaf ep^wmofogy 111 Community effects ol nonoccvpioanat tnmronmenul asbettm eipoture Amer I Pub Heahfc 5*1658, 196* 14. lundtn f l. et af Mortahry of uranium mined in million to odtatxm ripenure. haidrock mining, end cigarette smokmg--1950 ttrough September 1967. Health Phyuct 16-571, 19W 35 Davies |M- Bladder tumorgin theetearig-gpbleindustry. The lan cet 2-.14I. W6S 16 lee AM and faumen) If: Anciec end mipin orv cancer m min- An occupjrionat tudy. I Nat Cancer Ph i 431045. 1969 17. Achaton (0 . ft if Nim I cancer in woodnorters m it* furwnjre industry Brit Med f J S67, 196*. 1* VigHirf 1C and Salta G: Benienr and leukemia. New fng /Med 371 *72, 1964. Yt. Guard R er af MalignaM haemopartves and bersitne po>sorting Med iasoro 6271. 1971. 40 Aksoy M et at Acute leukemia due to chronic exposure to ben- acne Amer ( Med 52160. 1971 41 DtGpwm R l: tennne eapotuw and apUthc anema followed by leukemia IS years later. Semiannual report to (he Atomic Energy Commission. ACRH-19. Aigonne Cancer Res. Hasp. Chcago, IR. 196). p 11 Nuclear Science Abtkaett 17 No, 2*665 196). 42. KaNer H! and Metker H A Case of chronic myrlod leukemia af ter prolonged etpoture to br ncene. D M Med Wbch W11SS. 1961 4). form, A and Moreo l : Cytogenic Studies in a Cate of Bentene leukemia lump / Cancer 1.251. 1967 44 David A Attesting (he occupational chancier of leukemia in persons cipoted to betsiene. ftacoenf (ekarsbri 1611. 1964: Occup Safety Hearth Abt 1(2) 114. 1965. 45 focw A and Momo l : Oromotome Studies in a Case of ten- tene-tnduced frythrofeukerma furop / Cancer 1-159. 1569. 46 Hartwtch G and SchwamU C . Chromosome studies alter chrome bentene erposur* Ouch Med Wtchr 97 4S. 1972. 47. de Valters Al and Wtndnh iP- lung cancer in a fluorspar mining community t Radiation, d u ll and mortality espenence nt / fnd hard (94. 1964. 48 Parsons WD ef af. lung cancer in a fluorspar tnrsrg commumlv It Prevalence of respiratory symptoms and disability tor I Ind M*tf HO. 1964 49 lloyd BN long-term mortality study Of steelworkers V. Rrspiiatory cancer in coke plant workers I Ocrupaf Med 1) 5). 1971 ST 0095671+ feurnsf 1 Occupation*! MrdicitteTM 15. Ho. II/November 1973 90?