Document NNpO8Ro2Jx88Qjg6woEyvEzLy

Chemical Industry Instituteof Toxicology Vol. 8,No. 1 January, 1988 Studies on the Mechanisms of Chemically Induced Leukemia/Lymphoma Richard D. Irons, Department of Cellular and Molecular Toxicology Leukemias associated with potential exposure to chemicals or viruses are a major concern in modemsociety. The mechanismof leukemogenesisinrodents is poorly understood, making risk assessment of human exposure difficult. Studies at CllT are attempting to elucidate the respective roles of chemical exposure and retroviruses in leukemogenesis in order to evaluate the appropriateness of animal models for extrapolating risk to man and to provide information necessary to identify human populations at risk. that normally resides in the bone marrow. or viruses-invariably involve the The Author This "pluripotential stem cell" (PSC) is hematopoietic (blood producing) stem capable of either replicating itself or cells that reside in the bone marrow and ] ri r. joined the staff of ~ 1In 1 g~iving rise to any of the various cell types ultimately give rise to the cells of the Ja:uary of 1g-ffind iscurrently a found inthe peripheralbloodand immune blood and immune system. It is now senior scientist inthe D e p a f l m o f system. To appreciate this feat. one recognizedclinically that acute leukemia .Cemar and Molecular T-~W should consider that in the normal adult isoftenprecededmonthsoreven yearsby ma recognizedauthorityon blood the frequency of PSC inthe bone marrow functional abnormalitiesof the bloodand and bone manow toxicity and is is between 1 in l000and li in 10,000cells. bone marrow, and that bone marrow author of scient~f~cayertt~thce lebosne marrow replaces over suppression, aplastic anemia and and book,.hapten on the subject. He 10,000,000;000(10'') blood cells every myeloid leukemia represent a continuum holds membership In several day and is capable Of Increasing this or Spectrum of blood dyscrasias t c l e n t l f i c a n d p r o t e s s l o n a l Output as muchassixfold inordertomeet (abnormalities) rather than Separate or organizations, is pastchairmanofthe increasing demands. The Process unrelated entities. Since these functional l J l & T o x w m - S e c t i o n , a n d is through which this occurs involves a changes involve abnormalities in the a e m b c o _ fthe EPA Health Effects complex interaction of growth factors, growth of bloodprecursorcells.!heyhave Review Panel and the Toxicology a c c e s s o r y Cells a n d f e e db a c k beencollectivelytermedrnyelodysplastrc lnfomation Program Committee 01 m e c h a n i s m s t h a t r e g u l a t e t h e syndrome (MDS) (Galton. 1986). (he National Academy of Sciences. differentiation and replication of blood MDS describes a variable .but well- precursor cells and in turn the production 5 of mature blood cells (Fig. 1). (Continued on page 31 Leukemia/Lymphoma (from page 1) determining whether MDS precedes goal Yet to beachieved. However, itseems every case of benzene-induced leukemia reasonable t0 assume that at least one recognized set of blood disorders that remains an impassibility. It should be fundamental. lesion must involve have high propensity for terminating in pointed out that secondary MDS itself is Structural changes at the level of the 2 acute myeloid leukemia (AML). considered a neoplastic process and genome (i-8..a mutation)of the stem cell. Previously defined diseases that are included within MDS are aplastic or refractory anemia and preleukemia carriesa grave prognosis,with a mortality Certainly, the Propensity of alkylating of between 30 and 40% for those cases agents to cause leukemia, the prevalence that do not progress on to AML. .of chromosomal abnormalities. in (Galton. 1986). Frequent signs include: Evidence exists to indicate the great leukemias and their clonal origin provide anemia, leukopenia (a decrease in white majority of cases of .MDS and most 8 rational basisfor thisconcept. However, blood cells), and thrombocytopenia leukemias are the result of abnormalities since many leukemias are characterized (decrease in platqets). accompanied by originating within a single stem cell, Le., by what appear to be normal blood cells increasedcellularity of the bone marrow. they are clonal in origin (McCullocheta/., that are abnormally regulated with The rate of transformation of MDSto AML 1982). Studies utilizing cytogenetic or respect to growth and maturation, it has varies from study to study but is about biochemical markers to identify the been Postulated that the genetic 30% in "spontaneous" MDS and between origins of abnormalcell populations have information may benormalbut regulation 50 and 7Oo/o in MDS occurring secondary revealed that such clonal abnormalities defective. Inthis regard it is probably not to chemotherapy or benzene exposure. may be present for years prior to the insignificant that certain normal cells of The relationship between MDS and clinical recognition of leukemia. Thus a the hematopoietic and immune systems benzene leukemogenesis appears to be paradigmhasemergedthat implicates the (e.@, lymphocytes) have characteristics exceptionally strong, w i t h MDS stem cell in a multistep process that usually ascribed to cancer cells, such as preceding the onset of leukemia in ultimately leads to the presentation of the ability to replicate, invade other virtually every case for which data is leukemia. Elucidation of the molecular available (Bagby, 1986). However, events that precede leukemogenesisis a (Continued on page 4) SELF-RENEWING STEM CELL COMPARTMENT Schematic Dlagram, of Hematopoiesis I COMMITED I MOAPHOLOGICAUY I STEM CELL COMPARTMENT I IDENTIFIABLE PRECURSOR CELLS I MATURE BLOOD I CELLS \r II MYELOeUSI CROUYELOIXTE MYELOCnE METAMVELO- CWND PlTE GFuNULOCnE lwSuEwGMvCLuomc) ni I CFUGM I II___t II III YWCn*rrr II I U f W W M E Fig. 1. The production of blood cells involves the progressivematuration and replication of precursor cells In the boneqnawow. This process begins with the pluripotential stem cell (PSC), which has limited replicative ability but Is capable of self-renewal. Alternatively, it can differentiate to produce cells committed to any of the different bloodcell pathways. Dlfferentiation along a committed pathway is accompaniedby a progressive increaseIn replication such that the initial division of a PSC is amplified a billion-fold prior to the appearance of mature blood cells. .1.. Various assays have been described that measure stem cells by determining thelr ability to f o m colonies (/.e., colony-foming units-CFU). Several of these have been found to measure stem cells at overlapping stages In the commitment process.hsays that measure stem cells with the capability Of self-renewal Include CFU-S (spleen) and CFU-mix (or granulocyte, erythrocyte, megakaryocyte, macrophage). Assays that measure multipotential and committed stemcell populations Include: BFU-E (burst . forming unitsrythrocyte), CFU-E (erythrocyte), CFU-M (megakaryocyte), and CFU-GM (granulocyte-macrophage). I' .. Leukemia/Lymphoma (from page 3) inheritedas a "normal"gene by allfurther Infection Of a Target Cell by a Retrovirus progeny. Retroviruses inherited in such a tissues, kill cells, etc.. but that the number manner are called "endogenous" to 'VC a L and activity of these cells are normally distinguish them from exogenous or held .in check by highly effective and infectious retroviruses. None of the redundant control mechanisms. known infectious human retroviruses Since clonal abnormalities can be present for long periods of time prior to (e.g., HTLV-I, -11. HIV)areknownto target germ cells and thus to be transmitted . the onset of frank leukemia. there is vertically. Nevertheless. virtually all considerable likelihood that both mammals, including man, possess some hypotheses are cprect. It may be that DNA sequences encoding for retroviral structural damage to the DNA results in a elements. In some species, including heritable defect that conveys a man, endogenoussequences are rareand proliferative advantage on a target stem there is yet no evidence to indicate that cell, presumably via altered regulation of they areexpressed.However, it isa legacy any number of potential cellular ' of the great majority of strains of "oncogenes," but ultimate expression of laboratory mouse to possess numerous mg. 2AretroViruStargekandenterscells the malignant phenotype requires intervening influencesthat favor or select genes encoding for retroviruses. This by interacting with receptors on the cell includes the CDI, ~ 5 7 8 a~nd6 c 3 P~lasma membrane. Upon entering the for abnormal gene expression but are not strains as well as the 6 6 ~ 3 ~hy1brid Cell, the retrovirus releases its RNA Into necessarily themselves genetic events. frequently used in carcinogenicity the cytoplasm. A viral entyme, reverse studies. Certain of these endogenous transcriptase, catalyzes the synthesis of Viruses and Leukemia retroviruses are known to producea high DNA complementary to the Viral RNA, frequency of "spontaneous"leukemiasin which is then integrated into the cell's In John Steinbeck's tragedy Of Mice and Men, the mousestands asasymbolof man's inability to understand and control his destiny. To almost everyone involved in the study of leukemogenesis, the analogy is an undeniablyapt one. Murine models of leukemogenesis present perhaps the best opportunity to unlock the, mysteries of this disease. Nevertheless, the investigatorattempting to use these animal models is confronted with a puule of Gordian proportion. One of the culprits implicated in this dilemma is a family of retroviruses, commonly referred to as murine leukemia viruses specific strains of mice. e.g. AKR and C58 nuclear DNA. Thus the information (Hartleyetal., 1977; Chattopadhyayetal., encoded In the Viral RNA 1s Passed on to 1982). are implicated in certain strain- any daughter cells produced through specific models of radiation-induced subsequent division of the cell. leukemogenesis IC576U6. C3H and RF) (Gross, 1959; Giberman- and Kaplan, 1959; Kaplan, 1967; Upton et a/., 1958; and Leukemogenesis ationHaran-Ghera, 1976) and appear to influence the incidenceof 1.bbutadieneinduced leukemia in the 56C3Fl mouse (Irons et a/., 1988). In spontaneous leukemias of the mouse, the role of retrovirus is definitive (Cloydeta/., 1980). yet it must be said that the specific mofetchheanoisthmesr omr orodleelsploafyeledubkyevmirougseinnaensiys A number of chemicals and drugs are known to cause bone marrow toxicity in man or experimental animals, and it is therefore not surprising that they have been implicated in experimental leukemogenesis.These includebenzene, butadiene. ethvlene oxide. and a wide vbaerniezetyneoifs tahlekiolantlingoccaugents. To date, (MuLV). Retroviruses are RNA viruses that commandeer the normal machinery remains obscure. And in at least one definitel linked to~cutel~ukemi-aa of a cell to produce a complementary mleoudkeelm, ia3s-minethythlceholaRnFthrmenoeu-sined, ucneod Although seemingly unrelated, all of piece of DNA which is then inserted into the nuclearDNAof the cell. Once this pro- cboenevninecsitnagblirsohleedfo(Gr oroedtreonvoirwusanhdasLyet~ tchh~easreac~teargi~setnictss,inschoamrme onO:nTeheyOar ll emitohreer viral DNA sequence'is integrated into the 1984: Chinsky e ? a/., 1985). A distribute to the bone marrow in cell, it becomes a permanent part of its genome, encoding for the production of retrovirus (Fig. 2). In a great number of species, includingman, retroviruses have been implicated in many diseases of the blood and immune system, including characteristic to all naturally appreciableconcentrationsor give riseto occurring mammalian retroviruses, both reactive metabolites with relatively long exogenous (e.g.. HTLV-I) or endogenous half-lives in biological systems. These (e.g., M ~ L v )i,s that they do not contain a metabolic intermediates, in turn, are able directly transforming geneor "oncogene" to survive transit to the bone marrowand leukemia and acquired immune deficiency syndrome (AIDS) (Table 1). vipnirrouthpseeoirssaciolnsdtiloneguakcsecemoquoungetenfnoceer ssthi*semroulestofinthvaoenskyee adtirsireseucceta.ipnatebFrlaerocomtifonfutwhrteihthercpbeeirolslaspicnetitcvhateitvitoeanrgeooftr The first human retrovirus, T-cell lymphotrophic virus (HTLV-I) was alternative explanations. (Continued on page 5) discovered in 1978 (Poiest et a/., 1980; Hinuma et a/., 1981; Popovic ef a/., 1982). It causes adult T-cellleukemiaand to date ~~ appears to be restricted to southeastern TABLE 1 Japan, the Caribbean, certain regions in Italy. the southern United States, South RETROVIRUSESCAUSING PATHOLOGY IN NATURAL HOSTS America and Africa. HTLV-Iis an infectiousretrovirusthat is passed horizontally,Le., from one person to another. As such it is an exogenous retrovirus, capable of being transmitted from one blood cell to another, but is not '.. transmitted vertically from one generation to another through the germ cells. I f the target of a retrovirushappens to be an ovarian or testicular germ cell, the encoded proviral sequence will be Vlrus Dlseases 1. Fellne Leukemia Vlrus (FeLV) 2. Bovine Leukemia Virus (BLV) 3. Mouse Leukemia Virus (MuLV) 4. Simian L mphoma Virus (SLV) 5. Human {Cell LeukemiaVirus 1 (HTLV-I) - Leukemia, anemia, immunosuppression - Lymphoma - Leukemia. lymphoma - Lymphoma - Adult T-cell leuksmia 8. Human T-cell Leukemia Virus II (HlLV-II) -7. Equine Infeciious Anemia Virus (EIAV) -8. Visna Virus -9. Human Immunodeficiency Virus HislJocyl~c/reliculumcell leukemia Anemla Neurologicaland pulmonarydisease m sheep AIDS (LAV/HTLV-iII/HIV) . .., Leukernia/Lyrnphorna (from page 6) hematotoxicityand leukemogenesis. Am. model for the study of mechanisms of J. Ind. Med. 7, 447-456. chemically induced murine leukemia/ factors, including retrovirusbackground. Delore, P., and Borgomano, C. (1928). the regimenof chemicalexposure,and its Leucemie aigue au cowsde /'intoxication duration may be important considera- benzenique. sur lbrigine toxique de tions in carcinogenesis that have so far certaines leucemies aigues et leurs received little attention. Understanding relationsavec les anemiesgraves. J. Med. the relationship between chemical Lyon 9.227-233. t o x i c i t y , r e t r o v i r a l genes a n d Galavotti, R.. and Roisi, F. M. (1950). lymphoma. CllT Acfivifies 5(3), li4-5. Irons. R. D. Cathro, H. P., Stillman, w. S., Steinhagen, W. H., and Shah, R. S. (1988). Susceptibility to 1&butadiene leukemogenesis correlates with endogenous ecotropic retroviral background in the mouse. Toxicologist leukemogenesis will aid in providing an informed evaluation of both the appropriateness bf the mouse as a model for extrapolating risk of leukemogenesis to man and the relative importance of Erytholeukemic myelosis in benzene Poisoning. Br. J. lndus. Med. 7,7931. Galton, 0. A. G. (1986). The myelodysplastic syndromes. Scand. J. Haematol. 36. 11-20. 8(1), 2. [Abstract Mo. 71. Irons, R. D.. Heck, H.d'A., Moore, 6. J., and Muirhead, K. (1979). Effectsof short term benzene administration on bone marrow cell cycle kinetics in the rat. chronic high versus low level or transient Goldstein, 8. D., Snyder, C. A., Laskin, Toxicol. Appl. Pharmacol. 51,394409. chemical exposures with respect to S., Bromberg, I., Albert, R. E.,and Nelson, Irons, R. D., and Horan, P. K. (1978). human health. Such information is N. (1982). Myelogenous leukemia in Application %offlow cytometry for the critically important for the development rodents inhaling benzene. TOX.Lett. 13, e v a l u a t i o n of m y e l o t o x i c i t y in of sound regulatory and industrial 169-173. experimental animals. Toxicol. Appl. exposure policies. Goldwater, L J. (1941). Disturbancesin Pharmacol. 45,253. the blood followingexposureto benzol. J. Irons, R. D., Oshimina, M.,and Barrett. References Lab. Clin. Med. 26, 957-973. J. C. (1987~).Chromosomal aberrations Goodenow, M. W., and Lilly, F. (1984). in mouse bone marrow cells following in Aksoy. M., Erdem. S.. Dincol. K., Kepy, Expression of differentiation and murine vitro exposure to 1,3-butadiene. T.. and Dincol, G. (1974). Chronic leukemia virusantigensincellsof primary Carcinogenesis 8.11 71-1174. exposure to benzene as a possible tumors and cell lines derived from Irons, R. D., Smith, C. N., Stillman, W. contributing etiologic factor in Hodgkin's chemically induced lymphomas of RF/J S., Shah, R. S., Steinhagen, W. H.. and disease. Blur 38. 293-298. mice. Proc. Natl. Acad. Sci. 81,7612-7616. Leiderman, L J. (1986a). Macrocytic- Aksoy, M.. Erdem, S., and Dincol, K. Green, J. D. Carroll, A. S. LoBue, J., megaloblastic anemia in male B6C3F1 (1976). Types of leukemia in chronic Goldstein. B. D. and Albert, R. E. (1981). mice following chronic exposure to 1.3- benzene poisoning. A study in thirty-four Acute and chronic dose/response effect butadiene. Toxicol. Appl. Pharrnacol. 83, patients. Acta Hematolog. 55,65-72. of benzene inhalation on the peripheral 95-100. Bagby. G. C.. Jr. (1986).Theconcept of blood, bone marrow and spleen cells of Irons, R. D., Smith, C. N., Stillman. W. preleukemia: Clinical and laboratory CD-1 male mice. Toxicol. Appl. S., Shah, R. S., Steinhagen, W. H. and studies. CRC Crit. Rev. Onco/./Hemato/. Pharmacol. 59,204-214. Leiderman, LJ. (1986b). Macrocytic- 4:203-22.0. Gross, L. (1959). Serial cell-free rnegoloblastic anemia in male NIH swiss Bernard, J. (1942). La lymphocytose passage of a radiation activated mouse mice following reoeated exDosure to 1.3- benzenique. Sangre 15. 501-505. leukemia agent. Proc. SOC. Exp. Biol. butadiene. Toxicol. Appl. Pharrnacol. 85. Cathro, H. P., Stillman, W. S., Med. 100, 102-107. 450-455. Steinhagen, W. H..and Irons, R. D. (1988). Haran-Ghera, N. (1976). Pathways in Irons, R. D., Stillman, W. S.,and Cloyd, Short-term inhalation exposure to murine radiation leukemogenesis- M. W. (1987b). Selective activation of benezene produces myelodysplastic coleukemogenesis. In: Biology of endogenous ecotropic retrovirus in syndrome and leukemia in C57BL/6mice. Radiation Carcinogenesis, J. M. Yumas, hematopoietic tissues of B6C3F1 mice Toxicologist 8(1), 70. [Abstract No. 2771. R. W. Tennant, and J. D. Regan, eds., during the preleukemic phase of 1 , s Chattopadhyay, S. K.. Cloyd. H. W., Raven Press, New York, 245-260. butadiene exposure. Virology 161,457- Linemeyer, D. L., Lander, M. R.. Rands, E., Harris, R. L (1977). Testimony before 462. and Lowy, D. R. (1982). Cellular origin Occupational Safety and Health Irons, R. D., Stillman, W. S., Shah, R. S.. and roleof minkcellfocus-forming (MCF) Administration, U.S. Department of and Cloyd, M. W. (1987a). Selective viruses in murine thymic lymphomas. Labor, August 8. activation of endogenous ecotropic Nature 295, 25-31. Hartley, J. W., Wolford. N. K., Old, L. J., retrovirus in tissues of B6C3F1 mice Chinsky, J.. Goodenow, M.. Jackson, and Rowe, W. P. (1977). A new class of during the Preleukemia Dhase of 1.3- M.. Lilly, F., Leinwand, L.. and Childs, G. murine leukemia virus associated wtih butadiene exposure. J. Cell. Biocheh. (1985). Comparison of endogenous development of spontaneous lymph- 11A. 204. murine leukemia virus proviral omas. Proc. Natl. Acad. Sci. USA 74,789- Irons, R. D., Stillman, W. S., Shah, R.S.. organization and RNA expression in 3- 792. Morris, M. S., and Higuchi, M. (1986~) methylcholanthrene-induced and Hinuma, Y., Nagata, K.. Misoka, M., Phenotypic characterization of 1.3 spontaneous thymic lymphomas in RF Nakai, M.. Matsumoto. T., Kinoshita, K.I., butadiene-induced thymic lymphoma ir and AKR mice. J. Virol. 53. 94-99. Shirakawa, S.. and Miyoshi, 1. (1981). male B6C3F1 mice. Toxicologist 6, 21. Cloyd, M.W.. Hartley, J. W., and Rowe, W. P. (1980). Lymphomagenicity of recombinant mink cell focusinducing murine leukemia viruses. J. Exp. Med. 151, 542-552. Adult T-cell leukemia: Antigen in an ATL cell line and detection of antibodiesto the antigen in human sera. Proc. Natl. Acad. Sci. USA 18.64764480. Huff. J. E., Melnick, R. L., Solleveld, H. Kaplan, H. S. (1967). On the.natura' history of the murine leukemias Presidential address. Cancer Res. 27 1325-1340. Leiberman. M.. and Kaplan. H. S Cronkite. E. P. (1987). Chemical A., Haseman, J. K.. Powers,M.,and Miller, (1959). Leukemogenicactivity of filtrate: leukemogenesis: Benzene as a model. R.A. (1985). Multiple organ carcinogeni- from radiation-induced lymphoid tumor Semin. Hematol. 24, 2-11. Cronkite. E. P.. Bullis. J. E., Inoue, T., City of 1,&butadiene in 86C3F1miceafter 60 weeks Of inhalation. Science 227.548- of mice. Science 130,387-388. Leidenan, J., Stillman, w..s.,Shak and Drew, R. T. (1984). Benzene 549. R. S. Steinhagen, W. H., and-Irons,R. c inhalation produces leukemia in mice. Infante, P. F., Rinsky, R. A., Wagoner, J. (1986). Altered hematopoietic.stem ce Toxicol. Appl. Pharmacol. 75.358-361. K., and Young, R. J. (1977). Leukemia in development in male B6C3F1 mic Cronkite, E.P., Drew, R. T.. Inoue, T., benzene workers, Lancet 11, 76-78. and Bullis, J. E. (1985). Benzene Irons, R. D. (1985). 1.3-Butadiene: A -(Continued on page '. . .. LeukemiaAymphoma (from page 5) acute myelogenous leukemia (AML) been disappointing. However, as a (Vigliani and Forni, 1975; Infante et a/., consequence of recent studies all practical purposes, be reducedto two: 1977). Benzene-induced AMCs are conducted by Dr. Eugene Cronkite at either activated retroviruses and BO are predominantly myeloblastic (FA8 Brookhaven National Laboratories and - -independently leukemogenic, or MuLV is. C l aSS if iCat i0 n M 11. a Ith0 ug h 8 results obtained inexperimentsat CIIT, it co-carcinogenic, i.e., a significant Particularly strong association has been would now appear that these difficulties influence but not by itself leukemogenic established between benzene exposure have been largely overcome. in this chemical leukemogenesis model and the erythroleukemic variant of AML - Early studies at CllT revealed that (Table 2). These alternatives can be (FAB classification-M6) (Galavotti and toxicity of benzene or its metabolites to tested experimentally. In addition. it Roisi, 1950; Aksoy et a/., 1976). Further bone marrow cells *followed a pattern becomes necessary to determine how studies have suggested an association exhibited by certain cancer chemother- valid are mouse models of retrovirus with lymphomaaswell (AksoyetaL, 1974; apeutic agents that are toxic to cellsonly activation as predictorsof the potentialOf Manna and Polan. 1979; Bernard, 1942). at certain stages in their growth cycle chemicals to alter the biology Of From the results of these-nna (Ironset a/., 1979). m-portion of cells retroviruses, such as HTLV-I or HIV, in n safelv conclude U affected following exposure to such a human cells. Although little is known .occupational exposure to benzene is about the mechanism of HTLV-I a s s o d & a L d b an fic agent is governed by thecells in a sensitive phase, transformation, evidence st rangly bematoloaic neoplasms, Teardless of the dose of the compound- suggests that environmental factors DesDite the weight administered (IronsandHoran, 197 d z .influence latency in HTLV-I-associated implicating benzene as a leukemoqenn 'such agents, t h r regimen or neoplasms. and chemically induced alterations in HTLV-I antigen expression has been reportedin humancells in Vitro. sure may be the actual exposure.. By examining the potential of butadiene b m n e exposure and leu tigating the effects of or its metabolites to alter the biology of Althouah chronic exposure to 100 ppm,concentration and duration of exposure HTLV-I in human blood cells in culture. b-A- on benzene-induced bone marrow we hope to clarify the significance of the increas uppression in mice, Dr. Cronkite and his mouse retrovirus model to man and incidence of leukemia in man, the co-workersadoptedanexposureregimen epidemiologic findings that may Suggest significance of -re to low that deviated significantly from the a population at potential risk. In addition c o nc e nt r at 5 o ns o f b e n-z traditional lifetime exposure protocols to qualitative analyses of the effects of 6 0verSiaL A prevailing sentiment p r e v i o u s l y used t o study t h e chemicals on viruses in human and e n g clinical hematologists is that leukemogenicity of benzene. They mouse cells, it may be possible to blood dyscrasias indicative of bone exposed mice for 16 weeks to 300 ppm quantitate relative differences In species marrow damage frequently, if not benzene and held them for lifetime sensitivity at a Cellular level. This would invariably, precede the development of observation. TWO models Of benzene- be of considerablevalue in extrapolating secondary AML. Mowever, it preserltlu, inducedleukemia havebeendescribedby in vivo animal data to man. cannot be concluded 7Cronkite using this regimen: thymic Benzene &a. 6rereqwF-e. an a b s o l u t e lymphomdleukemia in the C57BU6 Thus, the mouse, a mouse known to carry MuLV cvidence linking blood dyscrasias or and found to have a high incidenceof this ince late in the last century, leukemia with exposure to benzene at tumor type fOllOWing radiationexposure: co&pational exposure to benzene has lower concentrations i n man is and myelogenous leukemia in the been associated with bone m a w controversial, and there i s little CBNCa mouse, which has a very tow l6&ty (SZFitesson. 1897). The most agreement among clinicians, epidemi- spontaneous incidence of AML but is frequently reported effects have been ologists. and researchers as to the known to develop a high incidence-of cytopenias (a decrease in one or more of significance of exposure to benzene at AML after exposure to radiation the different types of circulating blood low concentrations (Infante et a/., 1977; (Cronkite, 1987). leukocytes or white cells), anemia and Harris, 1977). It isnot known.forexample, Most recently, in experiments again pancytopenia or aplastic anemia (a whether bone marrow suppression, intended to characterize the regimen- severe and usually irreversible bone frequently seen at higher exposure dose dependence of benzene bone marrow suppression culminating in the concentrations, is a requirement for the marrow toxicity, we have obtained inability to effectively replace any of the evolution of AML, implying a threshold Preliminary results that confirm and cellular elements of the blood) b e l o w w h i c h b e n z e n e i s n o t extendtheuseoftheC57BU6mou~asa (Goldwater. 1941). The first report qf leukemogenic, or alternatively, whether mode! for benzene leukemia. In these .. leukemia associated with berum& there is no effective threshold for experiments, micewereexposed to looor 'exposure appeared in 1928Deloro and. benzene. This debate is not likely to be 300 PPm. either 3 or 6 daydweek for 12 Borgomano, 1928). yet benzene was not resolved w i t h o u t a n increased weeks *and held for observation. At -universally recognized as a human understanding of the mechanisms of aPProxlmately 6 months, MDS was leukemogen unt iI the mid 70's. leukemogenesis. encountered in animals in each of the Recognitionappears to have awaitedtwo Historically, such studies have been exposure groups. Included m the independent developments: (1) Although hampered by the lack of an appropriate Spectrum Of hematopoietic lesions scattered individualcases appearedinthe animal model for benzene-induced encountered Were not only T-cell literature, it remained for Aksoy et a/. and leukemogenesis. To varying degrees, l~m~homa/leukemiabut myelogenous Vigliani and Saita to provide the first investigators have been successful in leukemia as well (Cathro el ai-. 1988). organized studies of benzeneexposurein demonstrating temporary or reversible With thesemodelswe are nowaffordedan the workplace: and (2) this has coincided , bone marrow toxicity following benzene opportunity to investigate systematically with relatively recent recognition that exposure in rats and mice (Snyder et a/., potential mechanismsof benzenetoxicity ..;- MDS and AML represent a continuum or spectrum of blood dyscrasias rather than 1978: Snyder et a/., 1982a.b: Goldstein et a/., 1982;Cronkiteet a/., 1984; Cronkiteet to the bone marrowand leukemogenesis. The history of research in chemical separate or unrelated entities. a / . , 1985; Green e t a/., 1981). leukemogenesis suggests that numerous The principal neoplastic disease now Nevertheless, previous attempts to associated with benzene exposure is produce a useful leukemia model have 6 (Continuedon page 7) . .., LeukemiaAyrnphoma (from page 6) hematotoxicityand leukemogenesis. Am. model for the study of mechanisms of J. Ind. Med. 7, 447-456. chemically induced murine leukemia/ factors, including retrovirusbackground. Defore, P.,and Borgomano. C. (1928). lymphoma. CllT Activities 5(3). 1.4-5. the regimen of chemicalexposure, and Its Leucemieaigue au cours de /'intoxication duration may be important considera- benzenique. Sur I'origine toxique de Irons, R. 0..Cathro, H. P., Stillman, W. S. Steinhagen, W. H., and Shah, R. s. tions in carcinogenesis that have so far certaines leucemies aigues et leurs (1988). Susceptibility to 1.3-butadiene received little attention. Understanding relations avec les anemies graves. J. Med. leukemogenesis correlates w i t h the relationship between chemical Lyon 9,227-233. endogenous ecotropic retroviral t o x i c i t y , r e t r o v i r a l genes a n d Galavotti, R., and Roisi, F. M. (1950). background in the mouse. Toxicologist leukemogenesis will aid in providing an Erytholeukemic myelosis in benzene 8(l), 2. [Abstract tdo.71. informed evaluation of both the poisoning. Br. J. Indus. Med. 7.79-81. Irons, R. D.,Heck, H.d'A., Moore, 8. J.. appropriateness 6f the mouse as a model Galton, D. A. G. (1986). The and Muirhead, K. (1979). Effectsof short for extrapolating risk of leukemogenesis myelodysplastic syndromes. Scand. J. term benzene administration on bone to man and the relative importance of Haematol. 36, 11-20. marrow cell cycle kinetics in the rat. chronic high versus low level or transient Goldstein, B. D.. Snyder, C. A.. Laskin, Toxicol. Appl. 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