Document k6bNeo27Qagdby15vOpN7Dda0

FILE NAME: Avondale (AVD) DATE: 1973 Nov DOC#: AVD130 DOCUMENT DESCRIPTION: Journal Article - Recent Developments in Industrial Carcinogens Review Article Recent Developments /> --t in Industrial Carcinogens oo U3 Robert f. Eckardt M .D ., M l D. tn cn T h t topic of ca/cmogeos it one about which there it much confusion and a lio much m Hundenanding. `Thii in turn leadt to the development of lean and apprehensions. At tn clinical medicine, the w ord cancer in indtnliy immediately tcem i to lead to despair, whereat our approach should be straight forward and intelligent. I think of cancer in induttry juit at I d o about any other potentially toxic problem in in* dutiry. What w e need when a problem develops is knowledge-- knowledge of the process, knowledge of the chemistry, know ledge of the exposure The more w e know 0 more likely we are to arrive at satisfactory solution. In this respect, then, cancer in industry is like any other problem solving. first 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 "refabveiy" because tn 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 d o so. Thus the m ouse 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. Som e workers even use a microoipttte so that no nabbing 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 toxic it may interfere w ith their growth and w e know that this in turn wiH interfere with tumor development cause a skin-painting experiment rakes so long--u p 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 far none of them have held up when examined closely. Thus it w as found that tome carcinogens w ould cause atrophy of the sebaceous glands of the skin and this was once proposed as a " q u < W test However, in a study of 130 compounds, Bock & M u rid ' found that some car cinogenic com pounds did not cause sebaceous gland atrophy, white som e non-carcinogenic com pounds d id Some chemical 0> CduaX OwKior. *e S a l I m m S Avivan, t e e t r e i x S end itymwms ConyMi* So *V luidns Ml CTOIS 904 tests may have limited application, but because of the wide variety of chemical com pounds that have been shewn to have carcinogenic activity it would be anticipated tlut no single chemical test w ould have universal applicability. Suffice it to say that an expert panel convened to advise (he food 4 Diug Administration concluded dial there were no truly satisfactory short-term tests that had been sulficientlTproven that they could substitute for long-term carcinogenesis tests.' Some people h ive recommended that the material to be tested simply be injected or implanted s- hcutaoeously into rats or truce. This has the advantage of a known dote end minimal handling of the anim als.' But this method so fur has been shown to produce malignant tumors (sarcomas) in response to cellophane. Dacron, polyethylene, polyvinyl chloride, silastic, Pliofilm, Nylon, pofymethyl methacrylate, polystyrene. Suren. Ivulun, W -T, IHor\ silk,* and glass cover slips.' in our hands, w e found that a complex oil shown to be carcinogenic to the skin when painted caused a local abscess when injected subcutaneously w hich subsequently sloughed out without tumor formatiors Thus this route of testing may have limited application, especially if turnon are produced ai a site distant from the site of injection but if sarcomas at the site of injection are the only turnon 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 entire misconception Thus in the study of bladder tumors oc culting in workers in the dye industry, beu-naphthylamine, when administered subcutaneously, was show n to produce bladder tumors in dogs but not m mice In searching (or the reason for this discrepancy it w as found that both man and dogs excrete 2-amino-1-naphthol as a metabolite of beta- naphthylamme in their urine, whereas mice do not Dr. Ceotgianna Bonier, In England, concluded that maybe betanaphthytamme was not the carcinogen alter ail but the metabolite 2-amino-1-naphthol was. To test out this theory she Impregnated small wax pellets with 2-am ino-l-m phlhol and implanted them suigically into the bladders of mice. Sure ik enough, the mice developed bladder cancer. However, subsequenlly it has been show n that cholesterol, glass, stoanc acid, magnesium stearate, hexadccanol, ocradecanot, and naphthalene* the oM-lathioned moth bail) all produced blad der tumors and cancers when implanted into the mouse blad der. None of these are suspected of being carcinogenic. Thus this lest does not seem to be a very sound one. Incidentally, these studies of the metabolism of beunaphthylamine have ted to extensive metabolic studies and brisk scientific arguments about what truly is the caicmogemc agent. One school supports the 2-amino-l-naphthol metabolite a- iK - <ar<,r|.isj'i. ssf>icu* i rnjlhi-f (K-hevt-v that hydrin) laiioii m rU* n "<>'1 atom nr the am m o group (so-rallcd S t v in .station! 1- !h.-rardrw gcn, w hile yU nthr-fy bHtt-vr dll iircnt ate the true carcirtrgjen fh e v studies have h m i fascinating urn a biochem Kal standpoint and haw 't '. r O to k.-ep many c i i n * biochemists hrd at watt; m the Uboratu^. but probably do not h ive m uch p u t licit im plication lor indu.triai cin ert prevention Him evr-r 'h e studies <i the implantation o< cholesleroh staanc t a d end other materials into the bladder, previously mentioned. itw> hive serious practical con- sid eriin x tor other studies Thus drettwlerw ulvcol and other material* ire claimed by tame to be 1 carcinogen on the b in s thit they h iv e produced blidder cancers m mice. However, such tumors and o n c e rs never developed unless (m l 1 ^ted der stone s s it produced The question then irises-- is the chem icii i 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 c l because them is som e question that the experimental anim als may hive been infected with bladder parasite*, it is well know n tlwr Silharaia. a bladder infestation of hum ans by Schistosoma trematobium. is asiociaied with bladder cancer. In Egypt, where B ifh iizi* is endemic, bladder cancer incidence is quite high- The Schistosom es enter the body through the flan horn water in w hich the Egyptians are w alking in eating for thru fields from there they enter dvr bloodstream and ultimately end :ip m the bladder. Incidentally, the secondary reservoir for the Schivtosoma hematobtum is the snail, and m uch work is going on trying to find an agent that w ill kill the snail without producing other undesirable scological effects. The approach is like killing the mosquito to eluniisale malaria. Another approach that has been recommended to try to shorten the necessary test period for carcinogens is the use of newborn or sery young (suckling) m ice /ll was suggest* thtl 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 show n that this lest method probably has few true advantages * it may be that the use of newborn or ,ery young mice w as predicated on the ab sence of detoxifying enzymes m the newborn w hich sub. sequently appear as the animal ages. It is know n that a benz pyrene hydroxylase exisrs in the gastrointestinal tract," and it is further know n that newborns are frequently lacking enzyme systems that are present in adults. Even today, however, there are those w ho strongly urge tht new born 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 com bination of repeated influenza vuus in fections plus ozonized gasoline " or suitor dioxide and b e n zoU lp ym n e " or 7,12-d*nethyf-ben*(a)anthracene plus india in k " or, in hamsters, hematite plus beruo(a)pyrene" til have led to lung cancer production. The evidence indicate* that pure poiyaromanc com pounds Uk# beruofa) pyrene are rapidly removed bom the lungs. However, when introduced with particles or w ith SO r w hich may impair the ciliary )etAil 0) Octupaiioui Madicimfai. IS, Ns. llMovtmbsr 1973 ST0095672 itv n o .il nv-thim wns, n-siili-ncc- time w iitvn irv lur^; irwy t*. m u ih fxuimiKtt], and it n this inat-aved rm uk-nce tune w tv.h the cxprnrnriitehvls behevf- Inads ro the produttum <1 |UM^ cancer Ifu* penm ental w k on lung cancer is in its vw> early itagi-s. and it is loo soon yet to draw definitive sond o u o n s on it Ont- very interesting lung cancer experiment n m s was that sondusted by laslun e ra/ ." These workers exposed rat to 0 1 (fe n Id tw < hi.anm.aK.ti .atyu si hour, per day, live days p rfji' week itjt a tout of till exposures Nineteen our of 30 rats so exposed developed squam ous ceil cancers of the lung or can cers of (he nasal epithelium O f mserest m (Ins connsction is that subsequently in * Chemtea! plant in California where bn(cM orom M hyl) h e r w as produced several cases of lung C *n c W ife reported. I have only seen newspaper-type repots 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 fit lim e the ttaection of a carcinogen b ^ Jaboratory test* has subsequently beeiOofTowcd by th a u jvo itin cx gt cancers in humans. U sually eptdemioiogicjl studies have show n the presence of cancers in humans, and this in him has led to an intensnrt search in the laboratory far the carcinogen It is of interest that these workers have also been able to produce lung cancers In experimental animats w ith 2 .3-dtChloro-a-dioxane, ethyl brom oacetate, and f r em chlorbvdnn.** although these are week carcinogens. T h e / fit dem orw 'iMion of weak pulm onary carcinogenesis in anim ais/' / with these com pounds should alert everyone to minimize human expo- ares to (hem and to follow workers exposed to them w ith extra vigilance. for completeness it should b e mentioned that pulmonary Carcinogenesis in anim als has been demonstrated for beryllium." mckel carbonyl," and radioactive materials.1* In terestingly enough, inhalation pulm onary carcinogenesis has not yet been demonstrated in expenm enu! anim als lor chromates" or asbestos," although the f o m h\ prntmwl f n . m ahg.yn.lex when imecuid fnt/jm u^ylyrly" ifttragleuraffy." /-* *, and tht latter has produced pulm onary fibrosis (asbestosis) when administered by inhalation" and m alignancy when given intrapJeuratly" in animals. Finally, various epoxides, lac tones. and peroxy com pounds have been show n to have a car cinogenic potential." W ith this far-from-complete review of experiments) car cinogenesis w hich has been given only to emphasize the com plexity of the problem, I should now (ike to turn to som e in teresting recent epidemiological work. I shall not try to cover skin cancers in coal tar workers, m ule spinners, cutting oil users, wax pressmen, and the like, lung cancers m chromate workers, nickel refining, or asbestos workers (other than in sulators), bladder cancers in (he dye industry, nasal cancers in nick refining and isopropyl alcohol manufacture, or bone sar com as in radium dial painters because these have been covered in m y book" or other works. Presumably we arc discussing recent developments. M u ch publicity has been given recently to asbestos as a pulm onary carcinogen and producer of pleural or peritoneal mesothelioma. Actually pulm onary cancer in asbestos workers h is been recognized for 25 to 30 ye a rs" The condition was catapulted into prominence by the observations of W agner*7! South Africa am ong miners and processors of asbestos and especially by Sehkoff and his cowodrers" am ong m .uiaiion workers What has made Sehkoff and his associates' work 90S ST0095673 iia u u m I h is b- - i iht-ii u v n< union rtv unis li sillily thiv m n d 't'n n H-satjsi' m\uljtrws usually don't work fur om- single i-mplmi- hot rj'h tt most- (rum |ob to |nb wherever work is available inti thus w ink tiv multiple cmpliryeH, it wav very rliitirult to nbljm any kind ri picture of whet their health ex perieme h o i hern except through union recoeii When these w rte exam-nect it was found that of 612 workers w ho entered th tt'H f borote W ! and were traced through 1962. 45 had deal m earner of the lung or pleura O nly 6 to 7 men would hate boon expected to die of lung or pleural cancer if the nor mal incidence had prevailed Another interesting observation has W n that,ttv incidence of lung cancer am ong asbestos in sulation workers w ho smoke cigarette* is lar greater than for those w ho do not smoke." It h to be hoped that the industrial hygiene measures introduced among these workers w ill soon have this situation under control.* There is still some dispute among workers m this field of whether the asbestos is a direct carcinogen or whether its carcinogenicity is due to certain oils that may he present m the asbestos naturally or through Con tamination." " O f perhaps more concern has been the ob servation that asbestos bodies can be found in the lungs of a very high percentage of people w ho come to autopsy and have never been exposed to asbestos in their work.11 Although 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. Selikoff say in talks on the subject. As many people suspected, lung cancer incidence among uranium miners has been shown to be increased." Again, the nsk seems to be much higher among smoking miners than among nonsm oking tinners There have been 62 lung cancer deaths am ong 3.414 white miners and two among 761 non white miners Them -- tns lr> have been estabished a dosem pom e iela)irwhip which may Hopefully permit the elimination of Ihrs disease in the future Recently an outbreak of bladder cancers occurred among workers in the etectnc cable industry." This apparently resulted from the former use of beta-naphthytamine as an an tioxidant in the lubber sheathing used on the cables. Since this material has not been used by the rubber industry as an an tioxidant since about 1945, il is anticipated that these tumors wilt soon disappear However, it does poinl out the long latent period that can occur, and that in searchtng for etrologic agents m occupational cancer it may be important historically to go far back into the processes lo find the responsible agent Am ong 8.047 workers in a metal smelter works, 147 res piratory cancer deaths among 1,877 total deaths were report ed M The causa: e agent in this case w as believed lo be ar senic trioside exposures by inhalation, although some relation ship to 5 0 r exposures was also demonstrated. This recalls the association between sulfur dioxide and beoio(a)pyrene in animals demonstrated by the NYU group and previously d iscuss'd " A_ real surgrise has been the demonstration in England'1 of an increased risk of nasal cancer occulting in woodworkers in ihe lumiture industry Thts seems to be associated with the use of hsnf woods To date, no one has come forward with a good cu-ss to what the causative agent might be in this situation U rd-xihvdly, this observation w ill lead to extensive laboratory srud'es, both chemical and biological, m an attempt to ure <nve* (*- causative agent ' he xccumtjianon in the literawm of cases of leukemia following t>!Tinny expruum s***1 leads to the inevilable con clusion that Ivnaene is a leulcemngenic agent, pantcuUrfy in cases that have previously displayed a panmyelopathy Although this had long been suspected. the data repealed in the literature was nul sufficiently convincing to establish the leukcmngenk natuie of benzene. However, the more recent observations seem to establish this association beyond a doubt More recent observations of chromosome changes in workers exposed to ben m e " * lend further weight to the leukemogrnic nature of benzene, tn any event in our own operations we are proceeding as it benzene w as a teuken.ogrnic agent eliminating exposures wherever possible and reducing them to the lowest passible level where com plete elimination cannot be accomplished It has been teported" * that hang cancer Incidence In Poor- . ^ 7 f spar miners is 29 ernes 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 H is believed that this is the cause In this respect these lung can cers are similar lo those seen In uianlum miners and in Ihe okf (oachimstfwI-Schneebuig mines. A study ol lung cancer among coke oven workers in the sled industry" showed that they suffered a 2-1/2 6mes in creased Incidence of that disease. This increased to five times among men w ho worked topside on the ovens, and to ten limes if they worked five or more years fullrime upside. If is likely that exposure ro very high levels of benzo-a-pyrene and similar polycyclic aromatic com pounds occurred, although H is rjurte possible, due lo the compter chemical nature of coal lar, that other promoting or (-carcinogenic, such i s phenols or nitrogenous, com pounds have contributed to the increased in cidence- Undoubtedly, intensive chemical end biological studies ol this situation w in be undertaken w hich w ill In time elucidate the causative agents and their comparative significance. I have tried to develop lor you tonight some of the more recent developments in experimenal carcinogenesis as applied to Industrial problem , and some recent epidemiological 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 occupational toxicity problem. W e should study and become intimately acquainted with the processes involved, not sim ply by studying engineering or Row 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. W e should conduct appropriately designed toxicologicil less, in this case carcinogenic tests, un derstanding fully the limitations and pitfalls of any such tests we conduct. W e should carefully examine the workers in volved to detect early signs of exposure or early pre-canceroui changes. Thus appropriate urine or blood analyses lor nickel or chromium, or lor phenols in the case ol benrene exposures should be made. In some cases early biopsy or Papanicolaou smears of appropnale secretions should be undertaken At every opportunity, we should stress the avoidance of un necessary exposure I can think of no area where the '"operative efforts of industrial hygienists, indusinat nurses and industrial physicians can have a more salutary effect than in the control of industrial carcinogens and thus in the control of occupational cancers ""C Recent Developments in Industrial Carci*>r>sfEetr<9 H tterincei 1 .at )>, ami V ,,,,.K 1. a*t-i> t**1Utr*vi,.'/1 #f* mnyvn etui .>** cUnrh Camer Rev I f NI2. I**5*!! 2 Find ami r>mt Atlrarni<.ttaiiun V hixw Cummittee in PrtaKKift f-x Va'*A ( .r'-i.itiijo Pane! no can prv.*xni'< .port on finenr retfing o !* -.ari-n rsaiuati-rn nr i"-*f jd*tii.- and protKidet Tpxrcof & Appl Phirmj-rJ 30 4 W 1U' I I C 'f'n P rnd Cofbnf t kArvuw im f u frin u i t in tw in tl can tnn^i.ni; pn#Mnrv food Cmmet foxicnf 4 297. 1966 4 <)tK)nnS*tnur< 8S al I unfx-t tru'lim of polymer*. carcinogenic 4g*n'x to 4**n\|1t Cincn Apt 13 1)1 19)5 5 ^t*rl>>V. P r-f jf'Siudm on the Untetf) of petroleumwaxr*. 7o*of & Appl Phiat of 4 Supplement. 1962 f* ftm land . *i at Further experiment on implantation of maienah into IN* unninr bladder ol mu in i I Cantor 1* 575. 1964 I Pietia G RappaportH. *5 ShuNk P- TV *k h of carcinogenic themicaH in newborn truce Caver 14 300. 1901 9 Drill Pom G. Ute of newborn and infant animaK in car-, cinoanrnt texting food Cmmet Toaicof 6 24), WO*. 9 To>h 8 . and 5hub*. 0 Toxic effect of 7.12-dimethyl berutaianIhracenr n newborn and adult Swnt rrnce Mature 311428, 1906 10 Wallenberg tW rr i t tnnipriene HydroxyUt* activity m Ihr gattmxntextmal Iracf Caver Ret 221120, 1963 I I Wttriy DV ft if. The combined (Heel of repealed viral infection and M p m i* to carcmegenie aereaeft on pulmonary tumor induction m 0 7 black m t Amer Allot, for C tnctr Km Pioc 1378. 1961 12 Kuhhner M. and Utkin 5 Combined effect of atmotp h ev pollutant 10th International Cancer Confetence* HogtWn. Texat. May 19?0 11 5habad ls ' Experimental caver of the tune I Mar Cancer imf 2 lVK. 196) U 5affiotti U etaf bnnttricheal rmection ol particulate catcmogem into hamtmr tungt Amer Arroc Cancer Re* Proc 459. 196) 1) Utkin 5. ft at Tumon 1 the retptatory n e t induced by inhalation of git(t Hommethyf) ethpr Arch fnvmn HuHh 21:135. 1971 16 Inititute oI environmental Med***-. Reiearch m Environmental Health Science EighthAnnual Reportof ProgreJ* L/SPH5 Ceotef Granf ES 00260. Oecember 3t. 1971. p 68 17 Vonaid Al, Reeve* Al. and Urban EC) Experimental Berylkum fovenfogv in H I Stokinger f i d ). Seryfbum - ft* Induttrail Hygiene Axpectt Monograph of the Amer fndutt Hyg Attoc. and US Atomic Energy Commillion. Chapter 7. pp 201-234. New York. Academic Prr* 1966 18 5underman PW. and Oonnetty A| Meutlaiirmg pulmonary Aamnr m rah induced by the inhalation of nickel carbonyl. Amer / Pithot 461027, 1965 19 lisco H Dicuion at fhe Scientific Section of the Annual Meeting nt the American Caver Society. 1953 20 St-rfee CH. and iaetier AM HittopathotaR'C effect nf cfeomate chemical Report of ttudie* m abbit. guinea pig, rib. and mice Arch Environ Health 11 66. 1965 21 Vagner tC Abettoti in experimental ammaft Brit I Ind Med 20 t 1061 22 Pavne WW Production of caver in mice and tat* by chromium compound AMA Arch fnd Health 21 510, t960 23 Smiih WE, and lta*er RE A irantplamable meicxhelioma in duced bx aihevto fed Proc Part I 24 550, i%5 24 Van riiiuien *t el af Cjrrtnngetvrxv o ' apntxle*, lactone* and p'"WY nmpuunrh IV lum ** rm.piene m e|>rhekat a*d cunnectixe tnue in miie and rat I Mjr C aver fmt JT 21. I9XA 19529 filarth PI lrvfir*lr**f Parviongem Neuv Yv* C x o * llraiKwl 26 Annual Rnwt nf the Chief Impecior rf fjrtnn* (v the Year 1954 londnn. H M 5 0 Cmd 9605190-1. 1955 V YVagnrl 1C. > t i CA and stareSand T O -'u 'e pfetnat rmnmhi-linfna and atbettm expovure in the North 'Aevem Cairn Province. Rnr / tnd Med 12 260, I960 2d Selikoll II. Churg I. and Hammond EC AbMm eo<oure and VVXatta fAMA 118 22. 1964 29 Sekkott it ft af Asbettm exputum. muking. and neopfatia (AWA 204 106. 1968 10 5elikolf II. Program Duectri 'naufaimn ffygxtne Prog*et Repoap horn the Imolition Indutfy Hygxme Retearch Ptogtam 51 Harington (5 Occurrence of IH coexiifxrg ).4-bevpyrtne and teiaied w M x e n in n txtkx. N a M t 19143, 1963 12 Roe F(C at af Tumour inttiaiion by Vtural and tontamivhng aabectm w h umrnit I Cancer 1*91. 1966. 33 SeMtoff fl. and Hammond EC Environmental eptdwnmlogy Of Community effect* of nonoccvpananat ttxntpnmenul atbe*to* expoture Amer I Pub Heabh 5816%, 1968 M. lundin fl. et i t Mortality of uranium minen in elation to aih e n expovure. hatdrvk mining, end cigarette mokmg-- 1950 Rirough September 1967. Health Phyuct 16-571, 1969 35 Devin IM- gladder turnon in iht dearie-able induiUy. The U n ce! 2-.14I. 1965 16 lee A M end Faumen) |f: Anemc and >e*pwiorv caver m man- An orcupifianat iiudy. I N*t Ctitctr Put 42:1045. 1969 17. Agheton (0 . ff if M in t new In wtnhuarinf) in R futrxturt indintry grit Med f 1587, 1968. 18 Vigtiir 1C and Slit G: Beniene and leukemia. Mew fng/Med 171872, 1964. Yt. Guard R et af Malignant haemopattve* and beniene po>*amng Med Uvero 6271. 1971. 40 Alt*ay M et at Acule leukemia due to chronic expoture to bm- tene A m t ( Med 53160. 1972 41 DtGpwm Rl: letuene eepotuw and apUthc anema foilowed by leulwtilii IS yean later. Semiarmual teport to (he Aiernic Energy Commhvon. ACRH-19. Aigonne Cinrcf IU*. Heap. Clvcago. tk. 1963. p 31 Nuclear Science Abtkacp 17 Ntx 28665. 196). 42. Kahler H! and Metker H A Cate of chronic myrtad leukemia af ter prolonged expoture to beniene. O dd Med Wbch 86113$. 1961 4). form, A and Moteo l: Cytogenic Srurtet in a Cate of Bevene Leukemia (unop / Caver 3.251. 1967 44 David A Aliening the occupational character of leukemia m penont expoted to beniene. ftacovnf (ekerthri 161). 1964: Occup Safety Health At 3(2) 114. 1965. 45 forra A and Momo l: Oromoiome Studiet in a Gt*e of lentene-tnducad fryihrofeukerma furop / Cancer 5 -159. 1569. 46 Hartwich G and Schwamtt C. CfromOtame ttudift alter chrome bevene expmur* Ouch Med Wichr 97 45. 1972. 47. de Villen Al end Wtndnh P- lung caver in a fvonpit mining community I Radiation. dul and mortality experience nt /fnd hard 194. 1964. 46 Patton* W D ft af. Lung caver in a Ruonpif tnrtrg communth* It Prevaleve cl rmprratory tymptomt and drubihly But I Ind M*rf 8 HO. 1964 49 Lloyd M i long-term mortality tudy Of teciwork er* V. Retpirnlory ca ve r in coke pfam worker* | Occupaf A4ed 13 5). 1971 ST 0095671+ !cutl nf OccuD*licel HedictneWril 15. Hu. II/November 1973 90?