Document DGwJgDVpDz69n29LmZNKLKd1d

Benzene and Maiignanacs 1 BENZENE AND MALIGNANCIES Muzaffer h y ' N B r r A K ca~lm~ Depu~ncnrof Biology 41470-cebze-KocrdiTurkey Dtrringthcpcriodbetween 1%7and1~.90pmirnuwlcresnrdicdwho had different types o f malignanaes including 59 leatkm'as. I 3 lyvnp~mtzs.5 muitiple myelomas. 8 lnng cancers, 3 nrycloid meta- plrcicu.and 2 paroqsmal n o c n u d hcwvg&binuria Thr incidence of iatkanb in shoewo- exposed d m m i d y t o benzene in aperid of eight pan in Istanbul was 1 3 . 6 / 1 0 0 ~w,hich is sign@cantly higher thon thatfor leuknnia in the general popdodon. Folbwing the phaseout o f betutne in Istanbul. the.n u d e r cf leukemic wrkers decreased and none were reponed in three yean. Thr deveiopment of leukemia in pancywpenic pahnts with chronic benzene exposure was observed in 14 out of 59 individuals. Also studed wre 13 malignant [ymphoma. 5 mdtiplc myeloma. 8 lung cancers, and 2 paroxysmal nocturnal hemoglobinuria. The role of benzene in t k etiology of these maiignan- ciesis&cussed. Thc rehionship between diseuses and occqmiio~w~as enobiished by Rmnorini in the I7th century. Despite tldr long-swrdfng knowledge. the clfnicd discipline of occupational medicine mu initiated only recently. Among numerous chemic&. benzene is the only one which cnuses severe hematologic diseaes. Benrene is the parent arbon on en of the aromM'c group of chtmicais which stam not oniyfiom indusuiai sources but cllso is present in natural products. lncompiete combustion of natural p&ts c m ~ ~tehes fonwtion of benzene. Tobacco smoke also contains tract amounts o f benzene. According to Wailace (1989). smokers have breath concentration of benztnc around I4 pgln?, while for non-smokers the r(urge is around 2pgId. Benzene u absorbed via the inngs and approximately 40 or 5096 o f it isretained in the organs 4Etordhg to the amount oftheir lipid contents. The major organ systems inrplicarcdfor benunc mcrobolism are t k liver and bone marrow,in q t o c h m c P 4 0 . The mixedfrurcdon o w e s in the endoplasmic r e t i d m of thc parenckpa cells of the liver paform epoxi&tion of the n u c i a toform a r m oxide which drcomparcrtophenol und otkr nutuboiites. Recently it was shown ucperimentaityin Sprague-Dawley rats, Wister ntrs. and Swiss mice. [hathigh doses o f benzene cause a rapid decrease 1. COmrponCiing Aurh4r: !&zaEer Aktoy. TUBITAK Marmaxa Research Center. Depaxnnent o l Biology. 3 1 4 7 0 - G r b z a - W TURKEY. 2 Aksoy of colonyfonning cells (CFCI and toxc alterarton of the somark cells ofthe microenvironmetu Any agent t m c io plwopotent stem ceuS CM couuan aitcnnion in nvo impOrtanr c-iities ofthe U C s ( D u u r et d..198.5):I ) . A block or disnvbonce in seg-f-rentwolwin c m ~ waplam'c a n d . 2). A block in the long-tem differentiation to produce a vruiery of lineage rczrrictcdprogenitor cdls will cause ieu&cwtia. The purpose of this paper is to saumurize the malignancies due to chromc cxpanvc 10 benzene. MATERIAL AND METHODS During the period &om 1967 to 1990 a total of 90patients with malignancies due to benzene toxicity were studied. Frfty-ninehad leukemia. 13 malignanr lymphoma. 5 multiple mydoma. 3 myeloid metaplasia. 8 lung ODEQand 2 had paroxysmal nocturnal hemoglobinuria. Also srudied were 109 casts of q h c anmia resulting fmm chronic benzene exposure. Most of the patients were shoeworkers. but some were employed at other jobs such as print shops and railway npairplaces. Two were dyers and two w e n physicians in homone and hbmmks.Theamtcntofbenzeneinadhesivesandminnersustd ia theseocYqarioas w;Ls dctaminedby gasc.bKmmograpilyandmgedberween 8 and 83%. -talmethQdpw ~ statndafd RESULTS AND COMMENTS Following the epidemiologid studies performed in Istanbul (Aksoy et ai.. 1974).in Milan and Pavia (vigiiani and Forni 1976), in the US. (InEantc et .ia 1977; Rinsky et ai. 1981). and in China (YI~et al. 1987). it is impossl'ble to slrspea the validity of the Ean that benztne is a potent agent in hmnans. The has spvpaing thisassumptionarc the detailed Mow. The Incidence of Leukemia Among Shoe, Slipper, and Handbag W o r k s Exposed Chronicallyto Benzene in Isttmbd The use of knzentumtaining glpe-&csiVes in Lsgnbul SfaRtd approximateiy between 19Y and 1960. Shoes. slippus. and handbags were mandamred mostly in small and unsanitary workshops. Following the appeyance of benzenecontaining adhesives in the markct tbe shoeworkas rqiaccd their old adhesives with tfie new one (AL-soy, 1977,1988). Since 1961numaMls cases of chroaic bcnzcne toxicity such as leucopenia thrombocytopenia. and pancytope- nia have been noted in Istanbul. In 1968 and 1969 a hematological szudy was perfomred among 217 apparently healthy workers with chronic benzene exposuxc. Of these individuals 235%discfosed hemamlo@ abnormalitiessuch as IeaCOpenia. thrombocytopenia. and pancytopenia (Aksoy et d.1971). In 1960 to 1412.46 casesof benzene-mediatedaplastic anemia were investigated ( b o y et aL 1972). Among thun. 34 were h m small shoe-manufactraing workshops where benzenecontaining mmial was used. In addition, the benzenecontent of Benzene and Malignancies 3 88 adhesives and drinnas available berwecn 1970 and 1972 in Istanbul m g e d bawetn8 and 88% CTOpmoglu. 1972). Tangrin et aL (1967) describedsix shoe- wockcrs with scVere aplastic anemia due to chronic exposure to benzene in Istanbul. During this period 31 leukemic individuals wen found among the group mentioned The Qudc incideace of leairania in thcse siuxwolkcn was 1359 per lOO.OO0 ( m y a aL.1974a). The peak of kukania among the workers descri.bedabovewasxcaxdcdin 1973,and it was245 per lOO.OO0. Decline oftukemia Following P h a s w u of the Use of BertIcnr in Istanbtd The annual number of lnrLcmic shoeworktn with chronic benzene taxicity starcat to dccrcase following the prohibition and Iyartoaldiscontinuation of the meofbtllpnecontainiagadhcsives. 7'he occurrence of nu0 coscs of acute leukemiain a six year period in a tire cord f a t o r y In 1984 twouses of acurc leulotrniawere investigated, one myeloblastic and the second lymphoblastic.in a modern tire cord factory in h i t a dry very dose to Ismbul (Aksoy et al.. 1987). Approximately 550 workers were employed yeviy in this p h t where working conditions were usu;illy good and workplaces were large and properiy ventdatal Despite the good conditions, at one location the concennations of benzcne determined by gas chromatography (Varian) atone location in thc plant was 11Oppm and the solvents used in the aLlxiliaTy repair sbop were nearly 5% benzene (Aksoy et al., 1987). ?bus the inddenct ofIenlocmia was 60.6 per 1 0 0in~550 woljars in asix year period. Development ofLc&mia in Panqtopemc Padenu In our study comprising 59 leukemic workw with chronic benzene toxicity a prcccdhg pancytopenic period was present in 14 Patiurts, which is 23.7%. In addition,in a case with aplastic anemia with chronic benzcne toxicity. myeloid mcFapiati~hllowingastvenycarcanpluer#xlvoypaiod. I n d M h a f Sucepribiliry und GeneticFactors In our smdy of leukemia with chronic beaztne toxiciry in six patients. a famSal cwwctiOn was esrablished: two uncles, a nephew. and two'cousins. The father ofthe fifth leukemic shoewarka with benzene wrposme died in a hospital in Isranbul with the diagnosis of mtc myelalaosis. but rrevaluanon of the case repOKshowedthatthepatient with ctwnic cxpcime to benzene hadan midenti- ~~OfaculEknkaniZ The sixth IeSunic patitnt with chronic exposure to benzene had. like his son. chronic lympimd hkemia. Although he was never exposed to benzene. he used a long-time saccharine and colchicine. The role of these two substances in the etiology of chronic lymphoid leukemia is unknown.Thesesix leukemic patients among first and second generation rtlacivts constimted 102% of the leukemic paticnts with cfironic benzene txposurc.In ~YCSCsix patitno the development of leakania was possibly dut to the pmcnce of gene& or hainsic faaors. in addition to the presence of environmental deruminant This suggestion is in accor- 4 Aktoy daocc with the view dmt leukemia may be due to the combination of various itmimic andexoinsic factors (Gunt 1970). lndividval Susccpnbiiiry IndividualOB M y susceptibility, as f i t suggested by Rt&chncidcr (1922). has beencondaui as an importantfacoain tbe deveQpnenrof dponic benzene toxicity. Therc arc nummus examples in favor of asmmption. For example, two of the 64hbsm.u paritnuassoa*atcdwith aplastic anemia due to- baKmc mxi* WlCn bmllcrs (Alrsoy et& l975). Also, two pancytopenic paticno with c h n i c bulzcnc toxicity cousins n e catlsc of the variation in the i n d i v i d n a l ~ t oybsavedin C h O n k btnztne toxicity is obsam. Accordiag to Browning (1965). the m ~ sptrobable explanation lies in h e innace diffemcc in the ability of different patieno to carry Out the metabolic dttoxification.Some individualsmay be congaritally defiacnt in the W i t y to daoAfy benzene OB its membolitcs Inslcfficiency of Medical Supenision One of the leukemic patients with acute erythroleukemia was a 23-year-old shocwarker with 11 yeys exposure, who was d e d before the onset of h s hematologic malignancy. He was one of the 217 apparently healthy workus with chronic ucposure to benzene (Aksoy et aL. 1971). At that time, his hematologid data wen within nonnai limits (RBC 4.6mUmm3, Hb ll5g/1OOmi. hunatncrit 45%. piatelets 425.000/m3, and WBC 4.600/mm3 with normal diffatntial counts). To oar knowledge,in none dthe 51 workers associated with hematologic abnarmalt'ties in the smdy of 217 m t l y healthy workQs with chronic exposure to benzene did lwkcmia latudcvdop (Aksoy et ai, 1971). In conuast to this. the aforcmenaoncd wolkcr who was entirely normal in the previous smdy developed leukemia four yeys later. This case illustrates the innr(mv of medical supervision based solely 011 blood counts in individuals withchronic expasnre tobenzene. Dismbtuion ofthe Types of Leukemia in Chronic Benzene Toxcrry I n w g l y . there are signtficant diffcrcx~~erselaring to the distnbution of the cypesof l n r l o e m i a ~ w i t h c h r o m bccmcneexpasmc. Thesearr: 1. The difference in the benzenecontent In casesof acute leukemia. the percentage of benzene cancentmion was high. ranging between 9 and 88%. On the other hand. benzene content of the material in p t m t s with chronic lymphoid lcllkcmia was as law as 2.3%. 2 Adhesives which w m used by nmfy all workQJ with acute leukemia in our study contained only benzene. In conuast. the adhesives used by the pments With chronic lymphoid leukemia also contained 95% toluene. h o t h a patient with chronic lymphoid leukcmia was lata exposed to diffmnt chemicals. And. the pacient with hairy cell leukemia with chronic exposure to benzene later worked in a place where polysryrtneandpiyerhykne were used Benzene and ~Halignancies 5 Chronic Benzene Exposure. Malignant Lyw@owuz. Muidpie Myeloma, and k m g C'cer In 1960W m a n d B i c h e l l showed that rissutresponscscouldbe observed in lymphnodcs. spleen. thymus and born m a m w of rats after a singie injection of bewne. Recently Inw et aL (1983) showed what the e f k t of benzene administration in mice on lymphocyte function is at doses of the compound that produce little or no mc3sllr;lble difference in the circuiating cells. On the other hand. Aksoy published reports of six cases of Hodglan's d i s m in which chronic benzene toxicity might play a role in the development of ttus malignancy. harhermcat, we have studied seven more cases of different types of malignant lymphoma with knztmcxposum V i a n d palan (1979)pedormedacomptivcstndy on the morralityrateJ of different types of malignant lymphoma among workers with chronic benzene exposure. Their results were consistent with the possibility that chronic exposun to benzene might be imponant in the eriology of malignant lyxnphoma. Thertart stvaal studies sboanng ahigh m d t y fate from cii&rcnt types of malignant lymphoma among pathologistr. chtmists.and pasons who handltd~containingbtnocae, Mdtipie Myeioma In 1970 Tonu et aL nponed two cyes of multiple myeloma associated with chmnic benzeae urposrac. In 1980 Aksoy published rep& of four cases of mdtipk mycioma assamcd with chronic hmTac toxicity. fa one of these casesthere was ashonpaidof pancytopeniawith hypoplasuc bone marrow. In an epidemiologcai risk assessment study performed by Rinsky et ai. (1981) t k e mastotisticallysigntficant incrtase in death h n ltukuniaand mulhplc myeianarsptting~chronicbenoeneexposurc Laulg Cuncn In 1976a smdy by Aksoy, considaing five individuals with lung cancer associ- at& with chronic h e m toxicity, suggesrcd that there is a causal relationship between this chemical agent and this malignancy. In our study of d g n a n a e s dm to cfaMlic benzene exposure there wen eight cases of l ~ n gcancer. The ages ofthse paduus ranged h m 31 to 57 yeys and the duration of exposure was bemen'8and 35 yeas. In three pantnu. mild hematologx abnormalities such 6 Aktoy CONCLUSION Benzene is the only chemical which causes hematologic abnormalities md malignancies. In addition. there is no safe level for this chernicd. Therefore. benzene should be used d y when thae is no other possbilicy. REFERENCES AICSOY. M. (1976). "Lung ~ l l ancd c~fvonic benzene poisoning." Paper pscmd u the Pmc ku.Workshop of Toxicology and Beaztne. Paris. Novankr 9-11. AKSOY. M. (1977). Tutimouy before Ocerrpational Safely Health M m i n d m h (OSHA), US.aP.of Halth. July 2-5. AKSOY, K (1977). "LnJ;rm'uin workas due to occupational aposrpc to kntrrrc" NW kuDbul con^. CIh. sd 125L4. AKSOY. M.(1978). "Bcmnw a& laulranir"LeOrr to tfw Ediror. h c e t 1:441402 .AKSOY, M. (1979). " ~ 8 - L c u L a n o g c n i cEffects and Exposure Limirr." kt: .Opimiution of tfia w 6 6 Environment-New Trends. 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