Document NGw6pML7GVr0m6YBx0yb4Mryb

Invited Review The problem of b e n z e n e in outenvironment: clinical and molecular considerations HOWARD S. COHEN MICHAEL L. F R E E D M A N BERNARD D. GOLDSTEIN I24 MARCH-APRIL 1978 VOLUME 275 NUMBER 2 ' _c_ COHEN .DMA~ )STEIN enzene has found extensive comrn~&aI use in many industries including the lzath industry. both artificial and natural: th manufacture of artificial rubber; in gilding. bronzing and silvering. varnish, shellac. and paint removing; in the printing industry including rotogravure, lithography. m d pho- 4ography; a n d in dry cleaning.'-* Benzene IS a , constituent of high octane gasoline used in airplane and automobile engines.'A In add;tion, benzene has been used in the manufacture of expiosives, pesticides, plastics, synthetic detergents, conditioners. antioxidants, and rnedicinais.' Benzene is also iised 2s a solvent for rubber gums, resins, celluloid. -A-_l-though the to%icity~T.IFB&nzenweas noted I ,.as early as I837-biSantesson a n d much work was performed by Selling in-1910-19 16.' o n l y r u e n t l y have the toxic effects of benzene pained nationai attention.-'This was d u e to a n emergency governmental order icducing the permissible levels o i benzene exposure to one part per million in rne working atmosphere per eight-hour day from the previous ie\.eis of tcn parts per million.' For most of i n i s century. however. :he acceptable lcvels nave been considerably higher. "' Clinical Toxicity of Benzene Benzene toxiciry has been classified 3s two distinct phenomena. either acute or chronic. T h e symptoms otacute !oxicity have generally been related to the central nervous \?stem. The manifestations include muscle !rrmors. convulsions. salivation. nystagmus. and phenomena of very intense asphyxiation d u e to paralysis 0 1 the medullary respiratory center."'"' Chronic benzene :oxicity. on the dBER 2 T H E AMERICAN JOURNAL OF T H E !4El)ICAl. SC'IENCES I25 direct contact 15 achieved. the significant studies hake been variabte. Investigators h a v e toxicity is usually due to inhalation rather c than \kin absorption. found the marrow to be hypoplastic."-" normocel\uIar."'" and even hyperplastic"'" T h e principal metabolites of bqn7cne &re T h e effects of benzene on t h e Sone m a r r o w the phenols, 1ormt.d bv enrymatic hydroxFla- 1s of particular interest when one considers t h e tion.::':4* The phenols a r e then further pro- preterential distribution of benzene to this cessed by sulfation or glucuroniration t o give the conjugated end products."*"' I t has also organ. I_t _w a s shown ~ in- . dogs chronicaily ~ exposed~'_t_o-bcnzene_(blood levefs 1-2 _mp:dl) been proposed that quinones may be produced by oxidation ot the phenols.' that there was an approx.-imately %fold higher level in the marrow.' As the primary Based o n animal studies i t a p p e a r s that it :s entry of ben7ene is via t h e lungs. one would a metabo!ite of benzene : h a t :c responsible for expect it t o pass through the marrow belore hematopoleti< toxicity. This iubject ha.%kern reviewed by Snyaer.'" being presented !o t h e liver for possible detoxification. One might postulate that t h e The primarv elfect obsericd in chronic increase in benzene concentration found in benzene toxicity is o n the b o n e marrow. the m a r r o w is associated with the high l i p i d Renrene has ion? heen irrplicatcd as ha\ing solubility ofthe agent and the high proportion m a n y d if fer ent t o 'iic m a n 11e\t a11o n \ i ncl ud i n g of fat cells in this location. In considering [ne pancytonenia and Lipiastic anemia. acute eifects of :xnzene !oxicity on the hemato- mveiohlasric leuKrmia. mLsioid rnetaplahia, poietic sy.;tem. most studies have focused on and hemoi!tic anemia. The ;nost c o m m o n the circulating blood. A marked leukopeniais finding 1s pancytopenia.&O n e problem con- generally Issociated with benzene :oxicity cerning the relation of ben7ene to h u m a n irrespective ot t h e \ t a t u s of t h e ztarrow."'"' hematotoxic::y is :hat exposure usually oc- In one study benzene was demonstrated co curs to mixture of ioiatile compounds. decrease the proliferation of t h e rabbit rather than just to benzene alone. Despite-this. -- the overwhelming evidence points to ;in . association af hematopoie<ic discase- with -~ - benzene exposure-. r h e evidence includes t h e apparent lack 0 1 5uch association with other . ek n oNn v oI at I I e ;Lgen t s epidem ioIo i cal myeloid scrips within the marrow." This was found to occur at the myelocyte stage. T h e peripheral leukopenia might casily he attributed to :he short survival time ol these cells within the circulation combined with the decreased cntry of new cells. studies shoiving out breaks 01 hematotoxicity Abnormalities in leukocyte function have temporally related to the introduction of also been reported by a number of inves- ben7ene to an industry which respond to tigators. .Among the granulocyte ahnormal- replaccment of benzene with o t h e r solvents. ities which occur in mild benezene hemato- and the ability to produce bone marrow toxicity, and which may actually precede toxicity in various animal species exposed pancytopenia, are a decrease in phagocytic only to benzene." Much more information is f ~ n c t i o n , 'a~ decrease in leukocyte alkaline needed. however. concerning t h e effects of phosphatase a n alteration in other solvents on hematopoietic tissue and granulocyte and monocyte osmoticfragility," particularly the effects of combined ex- a n alteration of t h e fluorescent characteristics posures. of leukocyte nuclei," a n d t h e presence of t h e Pancytopenia has beec clearly identified as Pelger-Huet anomaly."-J7 i a consequence of prolonged benzene ex- Lymphocviopenia has also heen reported r posure. However. no t'igurcs are available 3s to be a common finding in benzene toxicity," f to the incidence of this disorder. Although and Goldwater has suggested t h a t this is ! human benzene hematotoxicity is often de- more common than leukopenia. Other inves- scribed 3s a n aplasric anemia. bone marrow tigators. though. have faiied to observe this ! I 2 6 U A K C H - A P R I L 1978 \'OLI:ME 275 U U U B E R 2 i COIIEN ET Al. a n d there have even been some reports of lymphocytosi,s. :*.io .Animal studies, however. have demonstrated 'effects of benzene on lymphocqtes and lymphoid [issues."'" Sny- der et have recently-shown that lyrnpho- cytopeniGwas a very early manifestation of toxicity in rats a n d mice inhaling 100 to 300 ppm benzene. There have also been findings su ggesrin g altered im m u n e irinct on includi rig leukocyte agglutinins," altered serum iin- munoglobulin"c)' a n d complement levels.'h and antibodies against leukocytes. platelets. and red crils in patients chronically exposed to benLene." An crffcct of benzene on 1ymphoc:;tes and the immune response raises t h t possibility that ben7me association with leukcmia might result from an altered immune function. based on the theoretical concept ol' the role o f immune sur\*eillance in carcinogenesis. In panicular. .wessmcnt of whether the effect is specific l o r t%o r T lymphocytes a ~ i dcvalua- tiun of t h e possible effect on huppressor lymphocytes which w e postulated to play a role \ n h u m a n ;Lpl;lst:c a n e r n ~ a " ~ 'should be performed. Still other 1eukoc:;te findings have been reported including an absoiute cosino- ill.(l a n d monocytosis with the presence of immature a n d abnormal monocytes" in the peripheral blood. A number of investigators have prescnted evidence oi decreased platelet iuncrion ~SSOCI- ated with benzene toxicity. "-" This appears to be d u e to intrinsic platelet abnormalitics which masnii'y the effect of a decrease in absolute platelet count. Morphological ab- normalities of both circulating plate!ets and thcir rnepiikaryocytic precursors have also bcen reported. In addition. there have been juggestions that abnormalities of co- agulation factors might also be 'The most frequently reported erythrocyte abnormality associated with benzene toxicity is rnacrocyrosis. Y , l L , : % .h\-oh I t is not k n o w n whether this inacrocytosis reflects an altercd stem cell population. an effect on D N A svnthesis. o r is due to some other red cell abnormality. Macroerythroblasts have been noted in the bone m a r r u w by Gornini et aib7 2nd hv Curletto and Ciconali,"" who also emphasired the marked poiymorphisrn and occasional giant multinuclear forms of mcgaloblastic ervt hrocyte bone marrow precursors. ,Macrocytosis of red cells has been suggested to be of prognostic importance'' a n d to he an excellent warning signai of hensene-induced hematotoxicitv in occupationally ex posed individuals. -0 However, inac- rocyric red cells have not been notea by all authors who have investigated individuals wIt h hen ze n e-i ndu ced hemar.ot ox icity. Significant hemolysis has been occasionally reporrcd In benzene-exposed individu- ais.''-' ' + 'including a few cases ot paroxysmal nocturnal hemoglobinuria."'"""' A It hou gh a n e m i a is usuallv d u e primarily to a failure o f red cell production. there may be a somewhat shortened red crll lil'e\pan in manv it'not m(J\t cases benzene hematotoxicit:;. i'his point shouitl he investigated further. Furrher cvidcnce that red ceils arc quaii- tatively abnormal in benzene-exposed in- d i v i d u ~ l sinciude rhe observation otabnorrnal erythrocyte incubated osmotic fragility de- spire normal values using the standard osmotic iragility test.1"'" There a r e also reports of changes in blood and urine porphyrin levels and arnmolevulinlc d a d . posslbly r e k c t i r i g altered heme synthesis. -'-'I' Of note in ihis regard are the reports of improvement in benzene-poisoned patients with pyridoxine." an essential cotactor in heme synthesis. e x It & Guirs-e-_gr-ee.5n.u-cIri-3s-ll-iv.n--i-anc cepted !hat increa-s-e--d.--i-n- c i benrcne denc-e o f- - - a%te .~mvt'lo_cenousleukemia and related Jisod-ers (eg. Gythroleukemia, acute inyelo- monocytic leukemia). The evidence t'avoring a causal relationship is not simply the more than IO0 case reports which, individualiy, could be fortuitous. S t r o-n.-g -sup_porIt .f-o..r !he causal role o i bcn7ene has been ob-ta_in-e.d in <ur\,evs--6~&rc& which-have historically had - suhsta ri;)naIV n -~Gf -i ni ui Gm bdteOr-sh<o$fGiVnedli,vidoufa5l s e occupan z e n e-i n T H E A M E R I C A N JOURNAL OF TIIT: SfE1)ICAI. scI1:Sc'rs I27 poorlv reg:iintcd circu:n\i ,init-:.. mo\t n o t a b l v 19 France l t m v , .ind 1 I I - K ~ V The evidence incl in udes Italv ,i!- ie t ob it w ,I r;ntion hv perhap\ Vi 20 g Ii;ini an :irnr> d Saita greater I c u k e m i a ~ i I~n khc.r:/cr;r.e?cposed workers than In [ h e general p(ip~iiation. and rhc r e p o n s b\ Girnrd et ai i n F r a n c e rer.ealing ,I signlicantlb g r a t e r p04iiivc tii\tory of hen- zene e.;posurc in paticnrj with acuie leukemia rhan in 3 control group.i l -7 V o r e reccntlv. Turkish investigators h a r e described at least :en cases of acute \eukemia.xv"'" mostly myeioblastic. Recentlv in t h e Ijnited Statey. anIntante 2 n d co-workers'" pertormeti epiiismiological evaluation o f u.orkers ex- ~~ po5eed !o Ttiu ic:el$ of benrene in t w o tactories. .- Thsse !nvri!igators reported .at leas7 ~a~fi1.e- foid incrcawti risk ottotai !eukernia a n d a ten- ioid :ncrc:ixetl risk ol' 2cutc m>eioblastic leukemia ( o r its .1 x i a n t myclornonocytic leukemia] i n L h c w \bor!-.er\ .\ccortfirigly. ;i ,xu5ai i:!atic>nsh\p between hcn7ene e x p m u r e and ,icute myeloblastic leukemia nppeary p roven. The as\ociaiion o f othcr types of !ctikemia b i t h benzene cxposure :s unclear. In some of the 1aigi.r collections < i f benzene-induced IcuKemia. including [hose o t Akso): e: a l in Turkey"' J n d Vigliani et a1 in Italr." c h r o n i c .Iymphocyiic leukemia has not been reported. In contrast. French investigators I-* -,q, -si 1 ha\.e rioted `I relatively high incidence o f chronic !ymphocvtlc leukemia. often exceed- ine that : ~ f acute mvelogenous leukcmia. Cases of chronic lymphocytic leukemia as- sociated with exposure have also heen re- ported elsewhere. including three from the Soviet Union.U4 Siniilarlv. the French have noted ;1 higher incidence of` c h r o n i c myel- ugenoux icukeF. although nut L Othe c.ytent of chronic 1ymp:iocvtic leuhernia. T h e reason for this difference is unclear. I t is conceivable that t h e nbserved association o f chronic lymphncytic leukemia with i)cn;rcne in France is fortuitous. O n e possible explana- tion would be the presence of nthrr \olvents ypecifically in the French workpl:iccs which could pos\ibly alter thc expression o I hcnJenc I ?R hematotox!clt:, The dbcer,L-cu Jifferencc: might also he explainable hv 3 longer lap phase for chronic Iyrnphociric !cukemia ankl the possibly longer henicne exposure of thy French patients in contrast I O the apparently more defined and recent rxposure ponuia- tion< investigated hv the Italian and Turki\h i n~3 es 1 1 g to rs . These e x p Ia II ;i i 1 ns a re. (7 i course. speculative. There is also inconciusive evidence Luggcsring that benzene ma!; pro- d u ce other I y m p ho pro I i f e ra t I\: e disor d ers , including ;lute lymphoblastic leukemia and m1>,inp ho a . .a- I I* f h i s would be consistent with a n apparent effect of hrn7cne on lymphocyte number and func;:on nbwrved in pancytopenia cases. In addition to cr,ronic mvelogenous ieukemia. a tew cases myelo- fibrosis 2 n d rn!.eloid metapia5is. a n o i her mycloprolifc:nti\ e Jisorder. have also neen reported. ""-' IU A 1t h n ug h occu pat i n n;i I c .P~OFu rc to hen - -I ~ ~ 7ene ;Ippears c a u s a f F r X i i e d IO acute m y ~ ~ - -_- ---______~ n$enous leuk emIa. a nu mb P r 0 T - l m port nnt - -questions pcrsist which ;ire c!ircctly pertinccr to permissible benzene exposure. O-f ~p~a~r-- titular importanc~e -is whether leukemogenesis occurs only after high.-dose heniene exposure ~~. . leading ~~~ ~~ to.. .zignificant bone. marrow damase. whether it can result trom any degree o f cytopenic stem cell toxicity. o r . less likely. is totally unrelated to the piincyropenic eifect o f benzene. I! - is p -. o_s_s_i-b-le that beniene or its toxic metaboiites directlv act aJs--carcinogcn on - bone marrow h.ez-aalop.oietic cells. .liternateiy t h e association with acute leukemia rnay represent a secondary manifestation of ben- Tene-induced pancytopenia that is expressed through an unrelated bone marrow aberra- tion producing a stem cell [hat is liable io a -- ~... f u n h e r muta.genic-event. Siich-ab event might occur m a n v y e a r.s..a..fter discontinuarion o i exposure. Benzene might therefore act as an initiator--& co-carcinogen. Support for these hypotheses. or any other (cg, benzene ac- tivates a leukemogenic virus) is conjectural. The lack o f ;in animal mndcl o f hcnlene- induced leukemia hampers studv of this issue. O n c posxiblv pcrtincnl topic is rh;Ir of COHEN ET A L preleukemia. This relatively poorly defined diagnosis has been frequently made in benzene-exposed individuals. Thereare a number of case reports of benzene-induced pancytopenia in which morphologically ahnormal prenegplastic bone marrow preclrrsor cells progressively developed. eventu-a-l..ly. re- sulting in frank acute leukemia."'""'^`"""-' Reported morphological abnormalities include bizarre red cell precursors which oiten have led to the diagnosis of erythroleukemia. The subject of preleukernia, including the effects of benzene, has been reviewed by Pierre.'"' The interrelation of idiopathic apiasric anemia, preleukemia. and acute leukemia has been noted by a number of authors. Ot interest is t h e theoretical discussion of D a m ashek'"' w h o added paroxysmal nocturnal hemoglobinuria to this group. This rare paraneoplasric condition. in H hich there is an a b n o r m a l population of circulating red cells derived from a single stem cell. may precede fir follow frank aplastic anemia. may end B S acute leukemia. or may transiently x c u r during leukemia states. Its reported occurrence in x m x k i t i o n with benzene exposure is further suggestive evidence 31' benzeneinduced pancytopenia being linked to acute leu ''Ib*' 'I' 51olecu lar Considerations Investigators havc tried to locate a nuclear lesion within the precursor cells 0 1 animals and humans exposed to benzene."'" ""! Chromosome abnormalities associated u ith benzene exposure in humans include ring chromosomes.' 'I) dicentric or :ricentric chrornosomcs. !iO and an egthroleukernic line w i t h a pseudodiploid karyotype v. here t h e t\vo E chromosomes were replaced with m a r k e r s . ,, " ? ' However, ii should be pointed o u t that even though studies have shown statis- tically significant increases in chromosomal structural alterations in h u m a n s exposed to benzene. most of these people had no detectable clinical abnormalities. When per- ipheral blood lymphocytes 0 1 individuals exposed to benzene were stimulated by phytohernagglutt ,in (PHA). chromosome al- terations were noted even though there were no detectable changes in the marrow.'" The chromosome aberrations included qualitative changes of both a stable and unstable nature (breaks. gaps) as well as frequently reported quantitative changes (aneuploidy. poly- ploidy). Individual variation was considrr- able. In studies by Girard'O and Forni.'" the significantly higher average chromosome breakage rates n i the exposed groups were attributable to a few individuals. It should he noted that although the chromosome altera- tions were more evident in those who showed initial clinical evidence of the ben7ene ex- posure. the changes had persisted both in the symptomatic and nonsymptomatic groups for many years after exposure. Recently. the etfects 01 benzene on DNA and K N A 3ynthesis have been studied." ?"I t was shown that in those animals which developed a pancytopenia. there was an associated disturbance ofthe D X A and RS.4 5ynthesis as well 3s c h r o m o s o m e aberra- tions." Eraluation of R N A bynthesis in rabbits using 'H-cytidine showed a ben7ene cffcct on the R N A synthesis o f fhe basophilic iiorrnoblast but not the pronormoblast." This may indicate a maturation arrest between these stases. It was further shown in micethat the hemopoietic stem cell was intact as derermined by in vivo colony forming assay.'' However. t h e nuclear integrity of this cell could not be determined by this technique. Experiments in rabbits using 'H-thymidine showed a marked inhibition of DNA synthesis with chronic benzene This was attributed primarily to an arrest of t h e metaphase sequence at the pronormoblast stage preventing differentiation ol' t h e baso- philic normoblast. These staging results are in accordance with the information available on RNA synthesis discussed earlier. Recentlv, studies in this laboratory have looked to the eifcct of benzene directly o n the translational level. Lee et alii' had shown that the incorporation of radioactive iron into INVITED HEVIEW, HENZENE 1% OljR FNVIROVMEST mouse bone marrow was decreased after ;L single subcutaneous injection o f henzcne. This experiment raises the question o f whether o r not hentene could directly affect heme svnthesis. :is heme is neccs3ary for initiation of protcin synthesis in most. if not all. cells Isce beli)w) this could he a Aite of toxicity to explain what ic scen with henzcne cxporure. Forte et JI'" have shown that benzene inhibits both human and rabbit reticulocyte protein synthesis tn c.rfro. T h e reticulocyte is an anucleaie cell. a n d there is no tranxcription occurring in this system. The rf'fect on prorein synthesis in rcticulocytcs. t herefore. IF d u e to a n i n h i h i t i o n of translation. T h e minimum concentration o f ben7enc necessary :o con- sistently inhibit protein ivnthcsis in t hcse ctud;cs w a s 438 m g l 100 ml ( 0 056 M).tiemin (50 g \ l ) prrvcntcd ;ind rc\.crsed [ h i \ inhihi- tion. This concentration L ) f hemin has pre- viouslv been .;how to maintain protein svnfhcsis in the abscncc d d c d iron- transtcrrin far heme \ynthcsis. ':' fkn7cne inhibition alsi)occurred when imn-tran3fsrrin for maximum cndogenous hemc synrhe\is was present. On t h e basis of these experiments it appears that hen7ene is interfering with endogenous heme \ynthcsis. .it hite other than incorporation of iron into the cell. The cifcct c ) f ben7ene a h was as~ociatctl with ;I rcverxible c o n \ c r s i o n o f polyrihosomcs to \ rnailer ;Igprega tes. pred nrni n ;in t 1y mo n o - riho\ones. These tindings are in agrccrnent with those of Trylintes"'"'" w h o found that rat liver yolyribosomcs disaggrcgarcd al'tcr injection ol' the animals with ben7eneat LI d o w ofO.52 to 5.63 mM. Thenumbernl'ribocomcs on messenger R N A is directly proportional to the rate o i initiation and inversely propor- tional to t h e rate of release o f ri bosorncs from mR S A . Thus, hen7cnc polyribosomal disag- gregation is consistent with a n inhihition of initiation with normal elongation and release. as occurs with heme deficiency."' This conclusion is supported by experiments show- ing that hemin both prevents and rcverses benzene- i n d uced pol y ri boso ma 1 di saggre ga- tion. as well as by experiments where benzene i failed to disaggregate polvribosoma when elongation was prevented by cyclo heximide. Direct demonstration of benzene inhibition of heme synthesis was also presented in t h i s study. It was o h s e n e d t h a t benzene inhibition occurred m o r e rapidly when either hemin \vas omitted from the incubation medium. o r when the cclls were made iron deficient w i t n an iron-chelating scent. Possible interpretations of this finding include rapid u p t a k e of hen7enc into t h e cells a n d direct inhibition of an enzyme rather than depletion of c'ndogenous iron. T h e interpretation that iron was not dcpleted \vas supported further by t h e reversal of polyrihosomnl disaggregation when ben7ene \vas rcmovcd 3nd the cells incuhatcd in the ahxcnce of either :ranIran$fcrrin o r hemin. I n order to m o w deiintti\cly de:ermine:he bite oi benzene inhihitinn o f heme synthesis. the following experimcn!s were ycriormed by Freedman et al.'!. Ren;.:nc f0. I 1 3 \I)was adrlcd i o rahhit rcriculocyte iicahatiocs afid both h e m e synthesis ( L.-2-"C giyc!ne incorporation) ;ind protein synthesis IL- 'C !eucrne incorporation, were found to be inhibited by approximately 5 0 5 . Hoivever. when the radioactivc precurcor uscd \viis 1-"C aminolevulinic acid (AI-:\). there was no signiricsnt inhibition of h e m e cynthcsis. Since .-\L.\ rncasurcs heme c!nthcsis beyond !he c n i y m e .A L.A-\yni hetase. :t was conciuded that %en7ene 15 inhibiting heme 5)'nthcsis at o r before this cn7ymatic ztep. Similarly. 1 m%l .\La-! both protcctcd against and reversed the benzene inhibition 0 1 protein synthesic. This confirmed both t h e interdependence ol' h c m e and globin synthzsis as well as the inhibition of t h e enzyme A LA-synthetase. When pyridoxine ( 1 mM) was added to t h e incubation mixture. there was also protection against the benzene inhibition of both heme and protein synthesis."' T h e active form of pyridoxine in cells, is pyridoxal phosphate. Therefore. in this system a t least ;Iportion of the pyridoxine has to be phosphorylated by the enzyme pyridoxal phosphokinase. Since pyridoxine was added in great excess. this COtIEX ET \L study did not differentiate between benzene bone marrow erythroid precursor system competition with pyridoxal phosphate at the showed that ervt hrapoietin stimulated A L A - site of ALA-synthetase. o r benzene comprti- synthetase and heme synthesis before any tion with pyridoxine for pyridoxine phospho- stirnul;itory ctfcct o n globin synthesis. l ' h a c kinase. Of note in this regard ;ire the investigators also s h o w e d that heme synthesis uncontrolled observations suggesting that is maximal in t h e earliest precursor cells and pyridoxiTe may be of thcrapcutic value in dccreases with cell maturity, while globin human benzene hematox icily." synthesis increases with cell maturity. These M o r e recently it 113s been shown that results ;ire compatible with the theory that elevated levels of intracellular cyclic A M P there must tirst be sufficient hemesynthesis to also prevent a n d reverse benzene inhibition of elevate intracellular hemin concentration. heme synthesis (and secondarily protein Sutficient intracellular hemin might then synthesis)." ' Cyclic .4MP has been s h o w n to reverse preformed H C R which would allow exert its protective eifect against inhibition o f protein synthesis irnd erythropoiesis to pro- heme synthesis at t h e level of ALA- synthetase. "* ceed. One possibility to explain this data is that benzene by its action a t o r before ALA- On t h e basis of these studies, Freedman ct synthetase. prevents h o r m o n a l activation of all'' have postulated that the primary toxic heme \ynthesis a n d derepression of HCR. effect of benzene might conceivably he which in turn is necessary for giohin synthesis inhibition of heme synthesis a t o r before and eryt hropoicsis. Furthermore. the hemin A LA->ynthetase. Intraceilulsr hemin has heen requirement in other cell types might explain shown to control globin synthesis by prevcnt- why thcre ia involvement of the entire ing :he formation a n d / o r reversing the marrow. activity ai a hemin-controlled repressor ;\n inhibition of :\LA-.iynthetase might (HCR) of initiation uf globin chain 5ynthesis. I I J,! ::I-ll: Hemin has also been shown to also explain !hc apparent differential d i benzene toxicity between :he sexes. In both be necessary for the synthesis ofglobin a h ikcil animal .mi h u m a n htudies. I'emales were as a large variety of- nonglobin proteins in many cell types.'"-''' I t appears that hcmin is shown to he .more sensitive to the elfec:s c ) f benzene. 'D*l4*:: n:h,:l :\[.,\-synthetase is a n in- necessary Tor translation of most. if not ail. ducible enzyme w h o s e activity is reiated to t he proteins. The reported effects on D N A and prescnce of various steroids. " I Etiocholan- R N A synthesis might then conceivably retlcct done. a metabolite o f testosterone. in the a decreased production of' the enzymes tor D N A and R N A synthesis. The effect <>n presence 0I' glucocorticoitis. greatly increases "'the iictivitv (it' .9LA-rvn :tase. marrow precursors other than erythroid cells This thcor!; is also consistent with the view could then result from a universal require- that toxicity with any inhibitor of heme I ment :or hemin in the initiation o f protein synthesis might n o t necessarily lead to aplastic I synthesis. anemia. I n order t o develop a p l a s t i c a n e m ~ ai t i n the past few years various investigators would he necessary to prevent heme synthesis have suggested that ALA-synthetase plays a in very carlv marrow precursor cells. Since 7 central role in erythropoiesis. Levere and A LA-synt hetase is t h e rate-limiting enzyme. e GidariIJ2 in 3 recent review, summarized the a n inhibitor would have to either affect this r data showing that erythropoietin and thej-11- enzyme or decrease the other enzymes in the H steroids stimulate erythropoiesis, heme and pathway below the activity of ALA- c globin synthesis in bone marrow cells, These synthetase. Benzene is a likely candidate to Y hormones appear to exen a major part oftheir af'fect early m a r r o w cells as it is highly lipid e action by primarily inducing the synthesis of soluble with a pronounced affinity for the .S ALA-synthetase. CIass et aii" in a murine I. bone marrow." 2 n?echan!\ms o ! concentration in the marrow, and t h e mechanism ot development of aplastic anemia And other clinical hematological conditions. Furthermore, :he interac!ron with other environmentai poilutants. such JS lead'" and 3lcohol.'?might -+-ccelcrare the dcLeloprnent 01 ber17ene t o x i c i t y . T h e r e Lire \ t i-i l i.n a n y cliiesiions t o he :~rt\wc:rd concerning hen7cne toxicity. What we have di.;cusse~i in t h i s - e \ i e w is a specuiativs t h e o r ? . :hat hopetully uiil \timulate !urtnrr research in !his l e r y 1rnp:)rtant Area. References I LVilqon R H . Hcnienc yoi\nning in indu\!ry i I d b Clin LIed >; 1517-151-1. 1942. ?. (;rcenhrrg !.. '.iarcr.; \ I R . (;<n/dna::: !. i': 2 ; ilcn7er.e fhcn;i)i! poi\oninp :n :ne rc>rovra+ure printine ind.i\trr in ';rw Yuru C'it) I Induhi H v < lilYlcn1 2 ; !US-420. IS3Q i.Hard\ H I . F.Ikinr ! I H : \ledical .,\nec:r - n a i l m u m allowahle concenirslionc Henfenc : I n d u \ t t i v g r t r r l c o i30: 1 9 h - x o . : 9 . i ~ 4 (ierartte ti W: Toxicological ~ t u d i e c,>n hkdroiarbonc II. \ c o r n p a r a t ~ s c.!ud\ <>!nIe effect 0 1 bcnycne Jnd certain r n o n o - n - a 1 i ~ l h c \ c - . r e n:c,n~ hcrni~pt~iccain\ d honc marrow r n c t a b ~ ~ i i \irnnrat\. AM4 .\rch Indust Hcilth I ? 4hX-477. 1956 5 . rammer? V A : rota1 svnthcsic hcnicnc and 11% derivatibcc as major g a ~ l i n c xtcndcrc Scrcncc I Y J:?3 I - 3 2 . 1976. h Wintrone XlM. I.ee G R , 130Cg.; L I R - ('linic,il Ilematr>lop. cd 7 Philadelphiii. I ca B I-rhrycr. 1974. p i745 Wolf M A . Kowe V K . ,WcColliTtcr 1)D et al: roxiciilouical xtudics o l ~ c r t a i nalkb lated hcni e n n .ind henrenc. : \ M A Arch Indu$! lfcalth 1 4 3 x 7 - 1?8. 1956. X. Erf I.A. Rhoads CP: Thc hcrnaroln~tcalclfcctc 01 hcnrencthcnroi) pol\oning. J Indu\t H \ y l o ~ ~ c o l 13 S;obcr\k W , Sicdlccka B. (;ajcw%ka Z. EEC; rcc;irding , n workers cxomed 1 0 Penzcnc corn- :oun:ir. Llcd h a c :4.277-:X!. 1977 14 Monacnkova A b { . Zorina I ". t i c r n o d ) n a m i L y And hcarr mu<cIc chanecc .n chronic w n r c n c poisoninR G i g Tr P r o ( Z a h l 19(4) 23-34, !9?5 15 Thicncs C'lf. bf3kv ?'J Cardlac ~ o i w n r i n (~3inicai Toxicology. s d 5 i'hildclphia. 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