Document 99NX2OpL76OxNMR8VXorB15K5

'- British Journ Haematol, 67:119-120, 1987. A Correspondence 119 ?pan. They also appeared in three cases that had received treatment against T. cruzi 5 years earlier. Cptrdra I1 de Histofogia HUMBERTOR. A. CABRAL Embnologia y Generim. F d t r U i de Ciencias Medicas. Universidud Nocional de Cordoba. C. Correo 362. 5000 Cordoba Argentina The ring cells in Chagas patients were found in 2.8% of total neutrophds (range 0-5-5%) in 200 cell counts. Their nuclei have two main forms: with and without lobulations. both with coarse chromatin.As fudgedby the difinentage of the patients. these cells would be produd throughout life REFERENCES Cabrai. H.R.A. ( 1971) P.AS.-positiVe substance in IymphDcyta of pattents with Chagas' disease lancet. i. 1356-1 35;. C a h l . H.R.A. (1983) Rhcumamid factors and Chagas' discas. Scknce. 219. 1238. Calbraith. P.. Mltus. W.J.G.ollcrkeri. M.& Damshek. W. I196 3) The '*infecttousmononucleosis cell'. A cytochemical study. Blood. 22. 630-6323. Langmhuiisen. M.M.A.C. ( 1984) Neutrophils with ring-shaped nuclei in myeioprolifaadve disease. tlritish lournlri of Hncmuwlogy. 58.22i-230. Peichev. iM. 1 1986) Ring cells in infectious mononucleosis. British luurnui 01Huemuwlugy. 62. 397-398. Santw-Buch. Ch.A. & A ~ o ~ tAa.M. . 198 I Immunology ofchagasic heart disease. imrnunopathogcnetic mechanisms. Clinical Immu- nology o/ ihc Heurt (d.by I. B. Zabriskie. M. A. Engle and H. ViIlamalL pp. 149-1ST. W h y . New York. Stavm. P.. Hloh P.F.. Vogt. E.& Van der Hagen. C.B. 11969) Ring- shapednuclciofgranulocyminpatient~vithacutee~hm~tulaemia. Scmdimwiun /uumolo/ Hnemuwlogy. 6. 3 1-32. I S MALE PREDOMINANCE (4/1) IN HAIRY CELL LEUKAEMIA RELATED TO OCCUPATIONAL EXPOSURE TO IONIZING RADIATION. BENZENE AND OTHER SOLVENTS; We read with interest the paper of (1987)in which he ported threecasesof&cdl malign- includingone hairy cell leukaemia t HCL)due to chronicexposureto benzene. Our recent 3-year study with alpha interferonIn H a (Flandrinef ul. 19871gave us the opportunity ofseeing. within a short period of time. a considerable number of patients with this rare disease. A strongmale predominance 14/ 1) had been noted in all series of HCL (Flandrin et ai. 1984) and we wondered whether there could be a link between male predominance Table I. Exposure to radiation and sabmts of H a patients according to occupaoon. Primary= d i m routine use or handling: h d ~=ysoivmrs muondy uscd in Work a m : ludgment =undocumented. but assumed. Profmion Medtcal a8 Garage mechanic driver Painter.decorator. mason 21 8 5 1 5 2 17 1 2 2 21 Prlntcr FannCr 32 1 10 1 1 5 12 ~sinccr other Total 61 1 1 12 49 3 2 2 1 5 12 24 r 105 9 13 18 5 4 12 17 36 120 Correspondence and occupation. Of a total of 105 HCL patients (Table1). eight were in medical professions (two X-ray kchnicians. one radiologist. two pneumologisrs. two orthopaediits a d an internist using radioscopyfor 15 years).Twenty-onepatients had jobs as garage mechanics or drivers or lorries or other heavy vehicles. Eight worked in the construction industry as painters. decorators or masons. Three patients were employed in the printing industry. particularly photogravure and equipment maintenance. There were 10 farmers and six engineers. The remaining 49 held various technical or office positions. We were able to reinterview 69 of the patients and obtain more details about possible exposure to ionizing radiation. benzene or other solvents. The persons in medical professions had all employed radioscopy. allof them for periods exceeding 10 years. Another striking &ding was the frequency of occupations in contact with petroleumderived substances. In the fvst place. there were garage mechanics and drivers who handle the maintenence of their vehicles. involving prolonged exposure and fresuent cutaneous contact with petrol or diesel oil (hand cleaning). As for the 49 patients whose vaned professions apparently involved no particular exposure. an appreciable number of the reinterviewed persons were discovered to have paraprofessional activities involving the use ofbenzene of other solvents. We have endeavouredto expressthe riskof exposure (ArpTtd. 1983), distinguishing different degrees of exposure (primary. secondary. suspected) and different agents (radiation. benzene. other solvents). Ionizing radiation and benzene have been clearly incriminated in myeloid malignancies(Goguelet uf. 1967: Aksoy et d. 1976).Their possible implication in lyrnphoproliferative disorders is not so widely acknowledged but has been supported by several studies (Arp et uf. 1983: Goguel el af. 1947). Some cases of lymphoid leukaemia have been reported among radiologists (Smith& Doll. 1981). A single instance of benzene intoxication coinciding with HCL has been noted in the literature (Bescol-Liversacet d. 1982). Of the 69 reinterviewedpatients. 52 adrmned expoke. either related directly to occupation or to paraprofessional activities. HCL has only recently been recogruzed as an entity and remains diflicult to diagnose which may account for these observations not being made sooner. Laboratoire Central d'Himutologie. H6pitul Suint-Louis. 75475 Paris cedex 10. France G. FLANDRIN s. COLLMO REFERENCES tursOy. M. (1987) Chronic iymphoid leukaemia and hairy cell leukaemia due to chronic exposure to benzenr rcpon of three case^. Britfsh \ o w l Of H ~ m a t d O g y6. 6.209-211. Aksoy. M.. Erdem. S. & Dlncol. C. (1976) Types of leukemia in chronic benzene poisoning. A study in thirty-four patients. Acta Haematolpgica. 55. 65-72. Arp. EW.. Wolf. P.H. & Checkow. A.Y.H. (1983) Lymphocytic l e m a andexposureofbenzene and othersolventsin the rubber industry. Iournal o/ Ckcuptional Medicine. 25. 598402. Bescol-Liversac.I.. Chabaux. C.. Bolinard. S. &Cuillam.C. (1982)Un casmixte&intoxicationbenzknique professiode etde leuchnie a trichoteucocyta. Toxicological European Rrscurrh. 4. 329-335. F l a n k C.. Castaigne. S.. Sigaux. S. & Degos. L (1987)Result of treating 53 hairy cell leukemia patients with alpha interfhn. Lcukmia. 1. 326-328. FlanMn. C., Sigaux. F.. Sbahoun. C. & Bodeae. P. (1984)Hairy cell Leulrcrma: clinicalprrsentationand follow-upof 211 patients. Seminars in oncology. 11,458471. Goguel. A. Cavigneaux. A. & Bernard. J. (1967) Les leuccmies benzhiquesdela RWonParisienneentre 1950et 1965.Etudede 50 observations.Nouvelle Revue francairc d'Himatobqie. 7.475480. Smith. P.C. & Doll. R. (198 1 Mortality from cancer and all c a w among British radiologists. British journal of Radiobgy. 54. 187194. tn view ofa number of minor errors. the following letter from British journuf of Huematofogy. 1987.66.279 is reprinted. ANNOTATIONS CONCERNING THE CORRELATION OF THE IMMUNO-PHENOTYPES OF LEUKAEMIC CELLS tN ACUTE MYELOID LEUKAEMIAS WITH THE FAB CLASSIFICATION The publication by San Miguel et uf (1986) about the correlation between cell surface marker analysis in acute myeloid leukaemias (AML)and the FAB classificationhighlights a crucial question. namely the exact correlation between the immunophenotype defined by cell surface markers and the morphological phenotype defined by the FAB classification. As a stimulus. we want to contribute a concise demonstration of our results in this field in order to provoke further discussion about the vaiidity of the immunotypefor a more precise specification of the FAB classification. We have analysed 136 cases of acute myeloid leukaemia classitid according to the FAB-system (Bennettet uf. 1976, 1985a. b) by applying the hmunoenzymohistochemicd method of alkaline phosphatase in 'sandwich' modification (Mason & Woolston. 1982) to bone marrow and peripheral blood smears. with the following panel of the 40 commercially availableprimary monoclonalantibodies(clusterdesignation. antigen mol wt. not available-NAk MY 4 (CDW. 14.55). MY 7 (CDW. 13.160). MY 9 (NA. 67-74). MO 1 (CD11.155/94).12 (NA. 29/34)-Coulter:OKT3 (03.20). OKT 4 (CD4.55). OKT 4a (CD4.60).OKT 6 (CD1.45).OKT 8 ( 0 8 . 3 1 ) .OKT 9 (NA. 90).OKT 10(NA. 45).OKT 11 (CD2. 401. OKM 1 (CDllb. 155/94).OKM 5 (NA. 88). OKB 2 (NA. 42). OKB 7 (NA. 175)--0rtho Diagnostics AML 2-23 (NA. NA). Ph4N 29 (NA,NA). PM 81 (NA. NA). PM 6 (NA. N A b Hybritcch: Hu-PI-m 1 (NA. 122/87). B1-3C5 (NA. NA). FMC-1 (NA. NA). FMC-10 (CDW 15. NA). FMG32 (CD14. NA). SRT-20 (NA. NA). 10B-1 (CD21. 140). PHM 6 (NA. AMERICAN 012760 Journal of Epidemiology - PLAINTIFF'S rnEXHIBIT .. Reviews and Commentary BENZENE AND LEUKEMIA L A REVIEW OF THE IaITERATURE A N D A RISK ASSESSMENT' HARUND AUSTIN, ELI LIB^ DEIJZELL. AND r m i r COLE T h e major purpose of this paper is to vicinity of the present occtipationsl stnnd- review the evidence. primarily epidemio- ard of 10 ppm. logic. pertaining ttr the re1nt.h Iwctwccn benzene and leukemia. Benzene is widely , BACK(;HOUHLI considered ta he a leukemogen for human In 1981, a Working Croup of the Inter- beings, but i t s potency is uncertain. Since national Agency for Research on Cancer low-l~vc*cl rpmurw tci trnlsnc chnmrtcrixc cnncltidcci Ilint t Iwrc. wtts siiTfic.ictit. @vi- mUtly f K ! C ~ l I ~ ~ J l ~W~Ll LJ iI Jl ~l ~~ ,i!. is imwrunL dence that benzene is carcinogenic ta hu- tr, dcterminc f a what. extent.. if at. all, law man3 ( 1 1. Spcclificnily. tlicy conciiidcci thnt. c*xp)ntirw itic.rcn.w lciikcmie risk. Mom- crposure lo hnzcne muy &maw lhe he- over. as we write. the ITS Oenrp,nt.ianaI mntnpict.ic .sv*t.rmnnri t lint wirlrnrc rrom Sitti.4 v r i i i t l I 1wil1 Ii Atiiciiiiiwr riii iiiii irc l i t i ~ ~ i i c l i ~ t i i i c i ql t~i t~d~i i wi ~ i-ni iil)lidw~81 I W i l M t i ~ 1empr.inc: tt) reduce workphce expomres relation between Iwnzene nnd acute mye- frririi it11 vii:tif Iiiiiir fitiii*.wcidltcd iwr*rngtn i w v t . i r l w k w i i i m In I.hr- w t t w n-prt..it.WJIW levci of 11) parts per million (ppm) to I noted Lhat. the evidence linking Lcn72ne ppm. This paper also includes an evaiua- with cancer other than acute myelocytic tion and critique of various risk assess- leukemia was inadequate. Benzene is in- ments of henzene and leukemia. These risk cluded on the list of carcinogens published assessment; were done for policymaking by the Secretary of the US Department of arid were developed to predict the leuke- Health 3nd Human Services 12) and is des- mogenic effect of benzene exposures in the ignated as a suspect carcinogen by the American Confcrcnce of Governmental In- Al~lircvtniiuiis:(-3. confidence intcwnl: pprn. parts dustrial Hygienists (3). per million: RR. relative risk. '/ ' Depmrcmenr ol Epidcmiolnm. School of Public Heaith. and t hc ('cimprchmtive Cancer center. the Univrrwcy 1 1 1 Al:iliamn at Rirminghnm. Rirnaingham. The present Occupational Safety and Health Administration regulation for exposure to benzene was established in $971 A L. and revised in 1974 (4). The rcmintion Rppriiri rmlin-rt* 1 1 ) I)r II , \ i t * 4 i i i . I l i m m i W.: TI{. ~ 1 . 1 1I I,rll. I Iitivi.r*itv i d ~\ld~i~IIiIiiIhiirminyhiiiri.t:ni- limits exposure to un ciglit.-lii~urtime- vcrwtv Statinn. HirminKhnm. A L .25294. weighted average of 10 ppm with B ceiling This wnrk urns qunpnnd in pnrt fw o grnnt from concentration of 2S pprn over a IO-minute the Natlonnl Cancer Inrtttuw. Unitcd StaWr Denan- ment t d lfrrili h dtntl Hiimnn S~WICtfM%2%Ar. ,ind period and a peak concentration not to in pan bv T c x a w . fnc. exceed 50 pprn for more than 10 minutes. '419 ...-I i' . s-. 4"U A W ' V I N F I ' At, This mgulation was established because of chromosomd studies is pertinent. Since h * n a n e was known to k n bone marrow these have also contributed to the evalu- depreusant and because uf its acuw toxicity; tion of the leukemogenicity of benzene. kn'zene was not generally recognized as a carcinogen at that time. Indeed. in 1974, A n i d sfdies the National Institute for OccupiAmul T h e carcinogenicity of benzene has been Saiety and Health noted that, although assessed experimentally in rats and mice case reports. chromosomal srudies. and sev- using several exposure methods, such as eral epidemiologic studies suggested a link skin application. inhalation. intragastric, between benzene and leukemia. the avi- and subcutaneous administration (1).The dence was not sut'fcient tu conclude that it International Agency for Research on Can- was a carcinogen ( 5 ) . However, in 1976, the cer reviewed these and other studies of National Institute for Pccupational Safety animals in 1982 and concluded that 'there and Health recommended that benzene be is limited evidence that benzene is carcin- regulated as a carcinogen because of new ogenic in experimental animals" (1).Addi- epidemiologic evidence (6). In that year, tional studies now have been reported, and the Occupational Safety and Health Ad- they strengthen the hypothesis that ben- ministration issued an emergency tempo- zene is an animal carcinogen which acts on rary standard for occupational exposure to several organ systems (9-12). However, this benzene which stipulated an eight-hour work has limitations which afect its nie- time-weighted average of 1 ppm with a vance to the evaluation of the nlation be- ceiiing level of 5 ppm for any 15-minute tween benzene and leukemia in human period. This became the Occupational beings. None of tne experimental work Safety and Hedth Administration stan- provides an adeyute onimal model for d u d in 1978 (7). However, a number of benzene-induced myelocytic leukemia. Al- organizations representing industrial con- though the studies have demonstrated the cerns obtained an injunction against the induction of n o n d i t hemtoiogic new standard. In 1980, the Supreme Court disorders by benzene, the carcinogenic ef- struck the 1 ppm standard, stating in es- fects are confined largely to nonhemato- sence that the Occupational Safety and logic tissues. In ratsand mice, for example, Henith Administration had not demon- benzene appears to be strongly dated to strated that the 10 ppm standard was un- the Occurrence of carcinoma of the zymbal sate ( 8 ) .Thus.a controversy remains about gland, a struaun with no human analog. the reasonable exposure limit in occupa- An additional limitation of the animalstud- tional settings and especially about the leu- ies is the lack of data on the potential kemogenic effect of low-level exposures. carcinogenicity of benzene exposures below SCIENTIFIC EVIDENCE 100 ppm. The potential adverse health effects of Chromosome studies Iicazenc have I~cciiC V U ~ U U L Ci~n cxpcrimcn- Despite several studies. benzene has not mi studies of animals, in investigations of been found to be a genofoxic (DNA- chromosomes, and in epidemiologic studies reactive) agent (13). However, it causes of workers exposed LO benzene. Here, we chromosome breaks and other chromoemphasize the epidemiologic studies he- soma1 changes in animals. and it has been cause they have provided both the qualitative and the quantitative estimates of the leukemogenic effecL of benzene on which risk assessnients and regulations largely suggested Lhat an excess of chrornosornal aberrations occurs among human beings exposed to benzene (1. I 1 1. Studies of workers with benzene-induced blood disorders have been based. Neverrhelebs. i~brief sum- have coiisistenlly shown on incmnsed pmvnary of the results of animal atudie9 and cilrnue ul' chromosomal aberrations in so- c r mnric ceiis. Hnwwer. studies of workers 200 to t l W ) ppm for wnrkers in the rotova- \ V h o Ir:ItI IIIW ( ~ 2 \ 5~ I I I~MI~ t 1 ~ . t * i \ ct** x l n w i i n w v i i r v phiti~s.\'icliriiii I*SI i i i i i i t v t t I l i r i l Ilit. i t i tir w h a ~huti no.overt siuns ol' chronic ben- citlence rate ot'acute leukemia among work- zene poisoning have heen inconsistent with ers heavily exposed to benzene was 20 times respect to cytogenetic findings. In addition. manv (ifrhrsc srrtdies are quite small. iind Irittst Ii;tvci 11it*1IiiHIitIii<ii*iil cl&*it*iic.ic*?r. i i r - clurfing inadequiilP assessment ol average higher than that of the general population. htit thig Psrimnw is not ndcquatelv docit- I ~ I t ' lVl t~l . ' h e epiciemiologic studies o f benzene and or cumulative benzene exposure. failure to leukemia are summarized in table 1. They adjust for age differences between groups. are reviewed briefly below. and no dose-response evaluations. More- In a hospital-based case-controi study in over. there are no data that establish a France, Girard and Rev01 (14) evaluated relation between chromosomal aberrations the association between twnzene and leu- a n d the subsequent development of leuke- kemia and other hematologic diseases. T h e mia nr other disease. cases were hematology seervice patients, of Epidemiologic studies whom 140 had acute leucosis (aim referred to aa acute leukemia in the study report), Elcvcn cpidemiolohic studies have evnl- 61 had chronic lymphocytic leukcmio, ond tinted t.he association hetween benzene and 56 had rnyenlpid leukemia. There .were also lvtihwiiiit ( I .I %I. 'I'licw* shitlics wtw. pn*- 124 c o n t m h Ivtmpilitliavl for noirIicinrit~t. ceded hy many case reports of leukemia logic conditions. Exposure to benzene and pnt icn1.u wit 11 inclwt rinl lwnzmc! exlwwirc tniiienc wn.p dctcrmind Ily cpicst.lming siih- and hv dcscriptiona of series of leukernin jects dwut chemicuis which they hnd tined cases associared with bsnzene exposure. during the 10-year period preceding the two of which have been updated by Aksoy hospitalization. Relative risks for benzene (29)in Turkey and by Vigiiani (30)in Italy. or toluene were 3.3 (95per cent confidence Akaoy (29) studied 51 leukemia cases. interval (CI)= 1.2-8.9) for acute leucosis/ identified in 196i-1983. among men occu- leukemia. 4.1 fl.4-121 for chronic lympho- pationally exposed to benzene in Istanbul. cytic leukemia. and L.8 CO.S-6.6) for mye- Turkey, and he estimated that from 1967 loid ieukemia. Tbis study suggeata a rtmng to 1975 the crude incidence rateof leukemia positive reiation bttwwn most forms of was 13 per 100,OOO person-yean among leukemia and benzene or toluene. However, shoe workers, compared with six per it does not distinguish between benzene 100,OOO person-years among men in the and toluene, and it provides no estimate of general population. However, the vaiidity dose-response. of t.hese estimates and the meaningfulness fahimam et ai. (15) cnnducted a m i d y of of the comparison ol the leukemia rates of 30.3 leukemia cases and 303 controls in .shoe wnrkers with those of the general pop- Nagasaki and Hiroshima. Japan. The study ulation are douhtfui because ascertainnient evaluated tmrtpctt.ionnl exposums 10 bcn- of leukemia cases was incomplete and was zene and to medical x-ravs: potential ex- not conducted in the same manner for the posure was determined on the hasis of sib- two goups. jects' occupations. The relative risk of leu- Vigliani (30, in Italy reported 11 leuke- kemia was 2.5 (95 per cent CI = 1.3-5.0) mia cases that occurred between 1942 and for persons with occupations invniving po- 1974 in Milan and 13 cases that occurred tential benzene or medical x-ray exposure between 19S9 and 1974 in Pavia among compared w i t h those with no such expo- workers in shoe 3nd rotogravure factories. sures. Renzcne expnsures were Lhought tn have The main limitation of this study is its ranged from 26 tn 600 ppm for workers use nccupntion as a surrogate for benzene handline qiues in shoe factories and from exposure. Each occupation classified as in- 4.1.) L.- AUSTIN ET' A L -r -2 n .i :Y c -C 3 a1 0 j;- Ia - .; 4 - -0 i I 3 5 a a .a. 424 I ACST1N L 7 A L vulviny poir.titiu1 Ix.tizc1ie rxpwurr uiuy prcliniiiiury liiiiliiip ol' u rctrcqxctivc 1111- have inciuded workers with no exposure to low-up study of 1.06 workers employed in ' benzene, as well rirl workers with exporurre the manufacture of rubber hydrochloride to chemicals other than benzene. In 3ddi- (trade name, Pliofilm) at three plants in cion. the relative risks were not reported two Ohio locahons. Rinsky et ai. (18) pre- separately for benzene 3nd medical x-ray sented additional results from this study in exposures, and no attempt was made to 1981. All workers with a t least one day'of quantify leukemia risk according to inten- exposure ~4 benzene during 1940 t h m g h sity or duration 01' Iienzene exposure. 1959 were inciuded, although most of the Thorpe (161 investigated leukemia inci- results pertained to the 748 men who were '- dence and mortality among 38,000 active workers and annuitants at eight European first exposed between 1940 and 1949. These men were foilowed through mid-1975. The affiliates of a large oil company. The obser- investigators used historical beazene er- vation period was from 1962 to 1971. Em- p u n monitoring data to describe expo- ployees were classified either as having sure conditions at the two'locationa~Al- been exposed to benzene (potential exposure for at least five years to refinery stretiins or petrolcum products containing at least 1 per cent benzene) or not (nodr though-these data were sparse, espdally for location z the investigatiii'belicved that exposure tended to be below the k- ommended limitx .- .- . w only occasional benzene exposure). The as- The mortality experience of the benzene- ' certainment both of benzene exposure and exposed workers was compared with that of leukemia occurrence was conducted sep- of US whice men. unexposed rubber hydro- arately by each of the affdiates. The ex- chloride workers at the study plants (n = * pected number of leukemia deaths was de- 398). and white male fibrous giass workers rived from the general population mortality in Ohio in = 1,447). The standardized mor- rates of the countries in which the a i f i h t e s tality ratio for ieulremia among the748 men - ,. were located. For workers potentially ex- who were first exposed between 1940 and ''8 posed to benzene, the stlrndardized morcal- ity ratio was 121 (95 per cent CI = 37-2051, 1949, compared with that of the general population, was 560 (95 per cent CI = 225- whereas the standardized mortality ratio 1.154). based on seven observed deaths. was 60 for the unexposed Using the fibrous glass workers as the re- This study has a number of limitations. ferent. the standardizedmortality ratio was Ascertainment of leukemia cases and doc- 473.There were no deaths from leukemia umentntion of exposure were inadequate. among the unexposed rubber hydrochloridp In addition, the report indicates that there workers: the expected number was not re- was considerable mcertainty about the age ported but was probably small. structure of the overall cohort. For these Five of the seven leukemia &a&'oc- reasons, the validity of the reported stand- curred among men with five or more yean ardized mortality ratios is questionable. of benzene exposure (standardized m o d - The standardized mortality ratio of 121 for ity ratio = 2.100). All of the Ieukemiaswere leukemia among potentially exposed work- of the myelocytic (acute, 4; chmnic, 1) or i*rh is ~ ~ ~ ~ r ( ~ t t i ~ i r Hk io~wl ~wiecr!.. the study is monocytic (acute, 1: unspecified, I) cell iieiLlrcr pcruuusivcly puuiLivc iiur ricguhc t y p . Aiiii~iigiiicii wlio Iiud lirnl I ~ v iIi-x 1m:iluseof the lack ofon analysis of leuke- posed to benzene between 1950 and 1959, r i i i t i iiiorldii y Iby i t i t h i t - t i c ~ t I ) i 4 t H I . Il i t . L O c r r ! wun w i t - ihiiIi C r o t i i I I I ~ & ~ I ~ I I ~ J I I1Ht e t 1 unexplained deticit of deaths from leuke- kemia compared wiLh 0.5 exyecurl min among the unexposed and the lack of Rinsky et 21. (191 have recently updated documentation of the methods used to this investigation. The updated study in- Itisitlct~tilyIcukiwii~i(1i*iiI11s :iitci III c l c * l i * t r i i i i i t - I ,t ~ t i i i i t ~ ~ tiit'ii W I I C I 11;vl I I ~ C I I c'xIwtsc(1 I C ) benzene exposure. lwrizei~rfur a~ leas1 u11r day duririg L'J.Iv- In 1977, Idante e t LII. ( 171 reported the 19ti5 and extends follow-up through 1981. e .. ., ... ... . . ... ." / The qtpdrrte also rises n jnh-exposure linkaae expected. Another d e e d worker hnd p t w d i i r e to Mbimnrr t h e crirnrilativc Iwn- myelomoncxy ic Icirkcmin. hut this wns nor zene expmute of' !.he mcn in the study. The certified as the underlying caw of deeth leukemia sbndardized mortality ratio for and was not inciuded in the mortality the overall cohort compared with the gen- analysis. The four leuke'niias were of the eral population was 337, based on nine ob- myelocytic cell type. Ott et ai. estimated an served and 2 7 expected leukemia deaths. incidence rate rntio of 4.4 (9s per cent T h e findings of the updated study are dis- CI = 12-11) for myelocytic leukemia for cussed further in the next section. benzene-exposed workers relative to the T h e study of rubber hydrochloride work- general population. ers is the strongest evidence availabie that The average cumulative exposure of co- benzene is associated with myelocytic leu- hort members can be estimated from data kemia. Even so, the estimate of the stand- presented in the updatGd report. Among a ardized mortality ratio for benzene-exposed total of 242 expected deaths from all caunea, workers is imprecise. Moreover, the study the cumulative exponure category wua 0- cuntains little nievant data on the txpo- 499 (midpoint, 250) ppm-months for 131 of sure levels associated with exccsa leukemia the expected deaths, 500-999 (midpoint, mortality. Five of the Seven leukemia 750) ppm-months for 35, and l.OOO+ (nay dcet.ha occurred a t lacation 2, for which -months tot .%. Thun, the n w r - * "Tmeaaurementa on benzene levels were par- ticulariy sparse. Furthennore, location 2 aisg*2ee5sc0tui'mmuataetdiv.ease5x5p4ospupremo-fmcoonhothi-t,-'m.o-remabboeurst was the site of several manufacturing op- 16ppm-years. The cumulative benzene ex- erations. including tire manufacturing. in ndditiun LO n r b b hyd-hloridt produc- pnmires wcrc Iowcr five of the leukemia thnn thin clues. -f-a- -r Lhrm -. of tion. I t is likeiy that four of the five men The mnjor 1imit.nt.ionsof this study ntP with lcukeniio ut Icmtion 2 had sbrted i t s small size and thus i t s imprecise esti- w6rking there before 1940, and one had mntc nC 1 hc d f r v t trrlwntrnr on Iliv inwir. rrtrtrtwl iii t!bt.t, I tviiwciv lirrn Imuvi i i w c l tin r t w w I)(' Iriikcirricr. 'I'lic crlmwvcrt.ion (.litit 1Iic . a solvent in tire manufacturinG therefore. mntrv I Iic. ~ t i i d vi n c d w r s fmm IIMXI i i w \ U I 2 mny have Ixen exposed to benzene in .<,cy departments other than rubber hydrochlo- L\/ ride. and their actual exposure levels may .I have k n underestimated. O t t et al. (20) conducted a retrospective follow-up study of 594 Daw Chemical Com- cumulative hen7me expsure of three of _ . Lhc? fivc Iccikc*tiiiri(:mwprthiiily WJIS IW~OW. I the average curnulathe exposure of the en- \2w 1 ,t i n cohort has several possible implica-$ :L. tions: th benzene e a re may be a threshold effect of mong susceptibles: the leukemias N.'' I ' - ' G,':'may not have been caused by benzene: or the benzene exposure estimates may have &. pany employees occupationally exposed to been incorrect. benzene in the production of alkyl benzene. Linos et ai. (22)evaluated the relation chlorobenzene, and ethyl cellulose. Men hetween leukemia and benzene in a case- employed in these operations from 19.38 to control study of 138 leukemia cases and 276 1970 were identified and followed-up controls. Any mention of a history of ex- through 1973. The study was updated to posure to benzene listed in the medical include no adtiit icmnl 362 pxposed employ- recnrris W:IS Ihe sole criicrim o f Irciizc!nc* e m . and follr)w-up w:is extcncfed Lhrough exposure. The relative risk was 3.3 (915per r he end of 1932 (21). Cumulative exposure cent CI = 0.6-28).based on four exposed to benzene was estimated for each cohort cases and three exposed controls. Three of mernher. The expected numbers of leuke- the exposed cases had chronic lymphocytic mia deaths were derived from leukemia leukemia. This study is larpiy uninforma- mnrtnlitv rates of all US white men. t ive because of the limited information on Four leukemia deaths occurred among henzene exposures and hecause of its small henzene-exposed workers. whereas 2.1 were size. Rushton and Alderson (23)conducted a en at seven plants. The study p u p incw-courroi study of leukemia wirhin a cluded men who had been exposed to ben- large cohort of workers at eight oil retiner- zene tor at least six months between 1946 ies in the United Kingdom. An earlier ret- and 1977. JobsNereclasaified as involving rospective follow-up study of these workers intermittent or continuous benzene expo(31) had reported A standardized mortality sure. For workers with continuous expo- ratw f h w leukemia oi 94.The case-control sure. cumulative exposure to benzene rticludrd 3ti leukeiiiia dcut lis which (ppm-months) wus cslculoted by using occurred among men employed between l e n e h of employment and the estimated 1950 and 1975 and 216 controls who had eight-hour time-weighted average for each worked at the relineries during the same job. Using the distribution of workers ac- period. Measuremenu of workplace ben- cording M a cumulative ppm-months ben- zene levels were not available. However, zene measure presented by Wong, the avstudy subjects were classified as having erage exposure of continuously exposed been exposed to low, medium,or high levels workers is estimated to bt about mmof benzene based upon their work histories. months (about 30 ppm-years). This correT h e relative risk for medium or high ex- sponds to a time-weighted average of about posurecompand with low exposure was 2.0 3 ppm, since the average duration of em(95 per cent CI = 1.0-4.0). The relative risk isure was 10 years. The m6&tfzStesof was not higher among men with high es- expami workers were comparedwith &oae posure compared with medium exposure, of US men and with those of ut'iotsmal and, furthermore, reiative risk did not ap- pear to be related b length of semice at the refinerim. T h e relative rirkr for the various - For the overail group ofexpcmed workers, there was a slight excess of leukemia &nth rolventa used in conjunction with knzcsnc. compared with US men (seven deaths, However, the informativenm of the study standardized mortality ratio = 117; 95 per ir limited by the Lack of data on exposun cent CI = 47-242). Four of th&I.eZ-_iZ-iG.*G.i-i levels and by the b n c e of any analyses were of the lymphocytic cell type, two were by duration of exposure or by induction myelocytic (bothchronic), and one was un- period. slpecified Among unexposed workers, there .Decoufle et ai. ( 2 0 evaluated the mor- were no leukemias, whereas 3.4 were ex- tality experience of 259 men employed be- pected (two-tailed p value = 0.07). The tween 1947 and 1460 a t a chemical manu- standardized mortality ratio for all causes facturing plant. Large amounts of benzene was similar for the exposed workers (stand- hod been used ;I;the plant, hut no meas- ardized rnonulity ratio = 87) and unex- urements of benzene levels were available. posed workers (srandardiled mortality ro- Employees had also worked with other t10 = 75). chemicals. These men were followed from Six of the leukemia deaths among ex- 1960 through 1977.There were three deaths posed workers occurred among men with from leukemia compared with 0.44 ex- continuous exposure (standardized mortal- pected (standardized mortality ratio = 682; ity ratio = 135; 95 per cent CI = 50-295). 95 per cent CI = 141-1.992). The cell types However. for these workers, there was no of the three leukemias were chronic lym- consistent trend in the standardized mor- phocytic, acute monocytic, and acute mye- tality ratio for leukemia over categories of lotnirni)c!ytic. either duraiion of exposure or cumulative Wung (5c)oiiductcd rl rccro:,pcctive Id- exposure. rrliliuugh ~ l i ch L c r tcvi lur trcud. low-up study ul4,602 male chenilcal work- using the nonexposed internal comparison P k n 3 c 3 - 3 d e a LI U it P n L e P 1' 12 h ti H il a e: 5 .II T P' iV dl T !I el e! st >I i11 lu BCNZF%E AND LEIXEMIA 427 group. yielded 3 one-tailed p value of 0.01. sion about the risk of leukemia associated The standardized mortality mtio increased with the low levels of benzene described. with Y C J n~inw~ fimt c-xlwmiim from .n vriliir Scvrrril cnw-crint rril sliiciie3 nf leiikcmiri of 0 for under 10yean to 182 (fourleukemia and solvent. exposures halve h e n ci)nrluctccl deaths) for n t least 20 yean. For men with within the rubber industry (27, 28,32.33). cumulative benzene exposure of at Ieast 60 Three of these studies were based on the pprn-years, the leukemia standardized mar- same series of cases from one rubber com- , tuliLy ratio wus 271;I)nscd on thrcc dcsths. p w v (27. 28, 32).A foiirt h srudv incliirlctl 7;). This study contains some evidence of a ,$ positive rplation hetween benzene and leu;L kemia. However. the overall standardized mar1;iiitv r:iiin of 117 for leukemia is not this series plus odditionnl cases from tlirrc other companies (331..Each study reported a positive association between lyniphocytic leukemia and solvents. This association ,. statist.icnlly sipificiint mid the slight. ex- $ - cess cndd he duc to confounding hy expo- w . sure to other chemicals. Moreover, the wiis prcrsctil. i n t m i y IIIW of I Iw fwir rril)l)t~r companies. and it was not. fmnd for other leukerniu ccll tyi)ca. I .strtdv is ton sm:iII tn prnvide nn ndcrpinte 'i ' ,?.' - . Y osscnwmc.t1t ol tIc)se-reqboiinc. lhwiiiw wi- ,::{\> exposed workers had a deficit of leukemia denths. no confidence can be placed in sta- T w o of the studies evaluated the relation IW'I.WI'CW 1yiiiphtwvI.ii- I c b i i k i a m i i i iliiti t*x;w- sure to specific solvents, including hnzcnc (27, 28). In the study by Arp et ai. (271, t.isticlnI tests nf trend which include the exposure to b p z e n e and to other solvents o r( *.\ iicivxliemvqi K r i t t q i . ~ i rwv-1 I 1ii11 n t w v I ~ii. wnn r l c ~ ~ t * r i r r i n tIrIiV liiikiitc s i i l i ~ . c . w~ o~r'k ' leukemia deaths among the benzrnc-ex- hisbricv wiLli historictil inftwiiiaticiii OII ?!! ~ I M W Iwcwkcm WIIS iicritc invcltrytic Icrikc- spwific:solvcnts iiwd in vnriniis w x k nreas mia furthcr detracts froni II cuuwil intcrprci :'. tation ofthe study muits. { '. Tsai et al. (26) reported the mortality .!; experience of 454 men who had been em- utitl prtK:casw. Siil~jt-c:t.u w c w rbiwifii*dIIX having 'primary" benzene exposure ii they had worked in areas where benzene was used and if their jobs entaiied direct hand- ployed at a n oil refinery between 1952 and ling of benzene or benzene-containing 90- 1978 and who had worked in benzene-n- lutions. Subjects w e n considered to have k lated production units. Review of industrial 'secondary" exposure if they had worked ;' hygiene data for 19.7. -3-. .1. 982 indicated that in areas where benzene was used but did the median exposure level in these units not have jobs involving direct contact. A was about 0.5 ppm. Comparisongrwpr con- sisted of the general US male population ; and a 10 per cent sample of nonbenzeneX , = exposed workers a t the same refmery ( n= 823). There were no leukemia deeths % .' -., among the worken exposed to benzene. w a n t itative levels of benzene exposure were not estimated. T h e relative risk of lymphocytic leukemia was 4.5 for workers ' ' with primary benzene exposure and 1.5 for &,workers with secondary exposure. Esti- ,-,.,, --mated relative risks for exposurc to sol- ' ' T h e expected numbers. based on general vents other than benzene were nearly iden- ,\ .) population rates. were 0.42 for all exposed tical to those for benzene. 4.5 for primary w n r k c n ;ind 0.2'3 for workers emploved for exposure and 1.6 for secondary exposure. benzene-related unit. Checkowov et d. (28) studied 11 of IIic here were five deaths from leukemia and lymphocytic leukemia cases included in the cancer among unexposed work- study by Arp et al. and 1,350 controls. ers, but no data were presented on the Benzene exposure was determined on the of deaths. Although this basis of employment in work areas where - of leukemia. its small . size and the relatively small proportion (36 per cent) of the cohort with an adequate follow-up period preclude m y firm cgnclu- benzene was used: no distinction was made between primav and secondary benzene exposures. The relative risk of lymphocytic leukemia was 2.S for workerswith benzene / . __ . . __ expIsure. E1ev;itt.d relative risks were q u t e l y in the rubber industry, an obser. found tor wiwkers exp)sed tu il number of vation which a h upplies to the prnxchorn- OlheT .W~WI~L.Si.ricludiar: .mume. cclrhon ic;rl industry tind to other industries in disultide, carbon tetmchloride. ethylace- which there is widespread exposure tu tare, hnd hexane. r n a n s s h e n t s . Also, because the xnajur per- These studies do not provide persuasive tinent studies have been small. little con - evidence of a causal relation between ben- fidence can be placed in available quanti- zene and lymphocytic leukemia among rub- tative estimates of the magnitude 0 1 m y ber workers. Tlie cr)nlideiice intervals of association: Measures of benzene exposure the relative risk estimates are wide, retlect- levels for relevant time periods are ex- ing the imprecision o l these estimates, and tremeiy sparse in all of the studies. There- they include the null value of 1.0.Moreover, fore, considerable doubt remains about the it is evident that these rubber workers were leukemogenic effect of benzene a t specific exposed to solvents other than benzene and exposure leveis and especially at low ieveis. some of these are associated with a relative risk of leukemia that is at leuvt as lar,=e as that for benzene. Because exposure c h i - mSK ASSESSMENTS .The expression 'risk assessment" de- frcation was not mutually exclusive with scribesthe final step in a long process. The regard to soivents, it is possible that the pmcess usually begins with an effort, often observed association between k&ne and based soieiy on experimental findings. in lymphocytic leukemia is due, not to ben- animals, to tieambe a dose-rcsponse reia-tLc zene, but to other soivenrs whose use is tion between a carcinogen and a cancer.' curreluled with rhe w of benzene. "lais phase of the p w e s uuuciily irrvoives In addition to the studies described extrapolation from observed, usually high, above, investigations of large groupsof rub- &se levels to hypothetical, usually low. ber workers (32. 34-42). newspaper web dost leveis. The process then continues by pressmen (431, and refinery workers (16, the making of a generalization to man on 31,44-55) evaiuated leukemia mortality or the basrs of the results in animals. This incidence, and some have found e.ccsIKs generalization involves a number of as- (32,34-37,41,43,46,48-51,53,54). Work- e n in these industries art'espiGd to Sol- vents other than benzene and to other chemicals as well. Several authors have noted that because of this, leukemii er- aumptions to equate both th.e -m-anner of wrdosing and the k e r ' o i responding of animrlr and man. These assumptions are us@y not subject to evaluation. In oth& instance;, the p'tocess o c@SM!!JlllllMll: flIlJh!f IInd il!fillCQf WtJl'&W?l assessment dim nol employ findin'gs Iron1 should xroc be r r ~ l r i h t dsolely tu benzene. ruiirurrls b u r~allicr uses epiderdogic. ~ I I - 111 t IN. iiEgtcgiitc. t IIC1qiiclemicilclKic evi- in- on human beings. In such insunces, illll\I~t'll~I' 3ll~:l':>l3 ,I i M ' t W4.1'11 IR'll?.l'llc* ; I l i a 1 Iiic iIiIliiwitit-n ol' IIir a t i i i t u r i 111 n u t i 1 gt'tb leukeIll1ii. However, this evidence is not eralization cue irrelevant. Norrarhrlr~~L.~ I C conclusive because it comes primarily from process may still lead to results of dubious the single teiatively small study by Rinsky validity. There are two common reasum Ibr CL 111. ( I!)). 'l'iic ot.lwr c1,iciciaioLlgic clcrt.ci thin: I I LIW~ ~ i i i d dti;Ictii ilre SOIIMU i t I l ( i 21 provide, ut Les~w, euk evidence 01' w causal the p w p k srudied experienccd quile Iiiyli association between benzene and leukemia. exposures so that some extrapolation is NO study rules out the possibility that oh- necessary to predict effects at lower doses. served associations between benzene and Efforts to describe a risk assessnient tor leukemia are attributalde, at leilsi in part, henzene and leukemia are in the second to confounding by solvents other than ben- category. There are little meaningtul am- zene. As urhcrs have poiiiled OUL ( 2 4 1 , this mal data. Dura for human beings are i , ~ possibility has n u t heen explored ade- and relate to uncertain, but probably rather h i d . expnsiirr! lcveis. Thus, effwts to de- be true of henzene. That is, there may be a scritw ilie extent n C small increases in lerr- level of henzcnc exposure below which no kemia risk ?s a consequence of low-level leukemogenic effect occurs. Thus,a lifetime exposure to benzene must lead to imprecise of exposure to benzene at 1ppm may entail resid ts. no increased leukemia risk. aithougha non- T h e benzene-leukemia risk assessments threshold linear model using a cumulative have used `linear" and `exponential" exposure measure might entail an apprecia- models to relate benzene exposures to leu- ble excess risk. A related problem in that of kemia. However. the use of such mathe- peak exposures. No adequate prwision is matical models obscures the fact that the made in the risk assessments for the poe- data are too sparse to provide an adequate sibly high, perhaps very high, benzene lev- description of the shape of the dose- els that may be unique4 harmtui. Thme response curve. Essentially, the results of intermittently high exposures are of 8peCia1 most of the benzene-leukemia risk assess- concern with respect to the Pliofilm cohort, ments can be well approximated by assum- a group upon which most risk amxsments ing that the leukemia "effect" is directly are largely based. There is evidence that proportional to the dose. usually measured these workers were occasionally exposed to as lifetime cumulative exposure. For ex- benzene levels high enough to require hoa- ample. if 15 yeam of exposure to IO ppm pita1izat.ion for aplaslic anemia (56). Thus, (150 ppm-years) of benzene is associated i t is plausible that the excess leukemia mor- with a twofold excess of leukemia deaths, tality obsen*ed among the Pliofilm cohort then it is assumed that 30 years of exposure was due to transient high expzsures. to 10 ppm 1.700 ppm-yenrs) o f henxene We do not suggest. t.hrrt cnrcinoycn risk would cause a fourfold excess.-This linear assessments are never useZul. However, in model is generally considered `consiiva- . the present situation of a risk assessment tive" in tbat itprpbably overistimat& theA for benzene and leukemia. there are special leukemogenic effects at low dotes. It must problems. There arc fcw human studies be borne in mind, however, that the validity relevant to an evaluation of the relation of a linear model in the benzene-leukemia between henxene and leukemia. and those risk assessments is not established. that exist are small. Thus. estimates of the The conccpt.nC a "threshold" is menninp- IciikcrnnCrnir cffwt of h n z r n c arc imprv- Tu1 lor the lmixenc-lcrrkcmiu risk osscss- cisc. An cvcn more wrioiis liinitiitiun is that ment.q and relates directlv ta the issue of the levels of henzene to which the workers what. const.iIt i t w u nicuningful m e s u m of in thew crhr)rts were expci.wd ore c.wnhtl- benzene exposure. Most of the benzene- Iy unknown. These ptwticular limitations leukcmia risk assessments are based on must I)(- consitlcred in the c m t c x t of tlic cumulative benzene exposures: these are more general limitations of carcinogen risk ohtained hy multiplyinv years of exposure assessments. A reasonable argument cauld by t h e average ambient benzene levels. be made that the data pertaining to benzene Thus. exposure to I ppm benzene for 10 and leukemia are inadequate for the pur- years is considered as the equivalent to poses of a meaningful risk assessment. exposure to 10 ppm benzene for one year. Nonetheless. such risk assessments have This miat hoc1 r d olitaitiing n sitmmnry c x . \,ern :inti p r n h h l v will continire I i i hi*donc. posure measure is used frequently in car- Five henzene-leukemia risk assessments c i n q e n risk assessments. the motivation are reviewed below. A n attempt is macle to being its simplicity. Nonetheless, it mav refine and to extend the findings of some not tw particularty menninaful. The human of them. W e also present our own risk hodv metabolizes and excretes with no ap- assessment. However. we emphasize that parent harm low levels of toxic substances by doing so we do not endorse the validity thnr are harmfill at hieher levels. This mav of ;I hcnzcnc-lecikcmi;i risk nssessmcnr rc- . ..- 43u AUSTIN o'r .IL *II~I..Wc wiali cuilv 11) t*iiiisiiIcr ilic vrrritius siisiuiiirrl Iiy metnlwm of the Pliofilm a)- assumptions ol'these risk assessments and hon r x p d in ppm-years (415-1,m LO r ? ~ d u a ttth:e extent to which their results ppin-years according LO White et al.1; and agree or differ. The White e t ai. risk maessrnepc d,, = the cumulative benzene exposure (expressed in ppm-years) for which an estimate of the excess leukemia mortality is One risk assessment has been made by desired. White et al. (57) of the Office of Carcinogen Thus, for example, if 1,000 men were Identitication and Classiiication, U S Oc- exposed in the workplace for 30 years to 10 cupational Safety and Healih .himinism- ppm oC benzene (300 pprn-years per nian). tion. These investigators used the so-called this modi~iedversion of the White et al. one-hit. non-threshold model. Although risk assessment predicts that between 18 this is an exponential mathematical model, and 101 of the exposed men will die from it is essentially linear in the range of ben- benzene-induced leukemia. This is as com- zene exposures considered. For clarity, the pared with a baseline of seven deaths results are approximated below by us with among unexposed men. Throughout the re- a simple linear model. The original model mainder of this paper we will use an expo- and our approximation produce almost sure level of 300 ppm-years to compare the identical results. results of the various risk assessments. This risk assessment is based upon the The standardized mortality ratioof 2,100 results of two retrospective follow-up stud- was obtained from the observation of five ies: the study of rubber hydrochloride work- leukemia deaths compared with 0.23 ex- ers originally reported by Infante et al. (17) pectedamong men who had been employed and hter updated by Rinsky et al. (18) for five or more years. White et al. excluded (hereafter termed thb Pliofilm study) and workers with fewer than five years of em- the tirst report of the study of Dow chemi- ployment because the eievated leukemia c d workers by Ott et al. (20). White et al. risk was observed largely among the Iong- considered other epidemioiogic studies of term employees. This is a pnjudicial justi- benzene and leukemia inadequate for the fication for excluding the short-term em- p i r p i s c ol' u risk uswssment. pioyees. A more defensible basis for their Using the assumptions of While et ai. exclusion is that over half of Lhese men hud regarding the findings of the Pliofilm study, been employed for less than one year, and the excess risk of death from leukemia (P,,)therefore had little bentene exposure. resulting irom a specified benzene exposure Nonetheless. White et al. do apply their is approximated by the following equation: ri.ik assessment method LO exposure dura- .tions as short as one year. It is inappro- priate to derive a model excluding the ex- perience of those with short exposure du- rations and, yet, to apply it to this very same situation. The ambient benzene levels experienced by the Pliofilm workers were considered to lit. (-qiiiilIII I IIV t Iiiw r w r v i i l rc*c.wriiir.nllc.tl standards. This assunipiiuli is coniruvcr- siril. liiiiiiltta et. ril. ( 5 8 ) mnintain that this asuiirpioii uvc.ccsiiiiiuics Llrc uc~uulIMI- zene exposures (and, hence. that their risk i kIla.sl'!i..)lIII'III III I1 I i * n * n l I llrllt'n t'%l*l'RN 11'1 I 11 rnia ml)rtillity). Others (59, 60) lwlieve thni Il i t - t i c ~ ~ i t r li ilcvizi*iic* t - x l b a ~ m i i r t ' , , wt*rt*t . l ~ i i . , i t l c erahiy higher than the recommended %tan- based nn only three leukemia cases and so chrds. A paint of agreement is that the is very imprecise. actual henzene exposures sustained by members of the .Pliofilm cohort are un- The International Agency for Research on known. as Infante et al. (58) recognize. This Cancer risk awesaqnb uncertainty a h u t the benzene levels is the The International Agency for Research major limitation of a risk assessment based on Cancer (1) also h3s estimated that hen- nn t h e Pliofilm cohort. White et ai. ob- tene levels similar to those experienced by mined 3 lower bound for the average ben- men in the Pliofilm cohort are likely to zene exposure (413ppm-years) by multiply- cause an excess of 140-1iO leukemia deaths ing t h e average recommended standards for per 1,000 men exposed for a working life- 1937 through 1954 (83 ppm) by five years, time. The estimate of 140 e s e s s leukemia the minimum employment duration. The deaths was obtained by considering that upper bound for the average benzene ex- those men who had been employed for a t posure (1,500 ppm-year) was obtained by least five years had experienced a 20-fold multiplying the average recommended excess in leukemia mortality and that the standard for 1937 through 1975 (50 ppm) risk that a man will die from leukemia in by the maximum length of employment, 30 the absence of benzene exposure is about years. These bounds cover a broad range of seven per 1.0oO. The same assumptions benzene exposures and neither is likely to were made by White et al. (57). The inter- accurately describe the benzene exposure national Agency for Research on Cancer of a typical worker. It is unclear why White considered this estimate a lower b m n d for et ai. did not estimate individuai cumula- the risk associated with a working lifetime tive henxcnc exposures by multiplying c3ch (45 years) nt similar IeveIs. However,it can year of employment of each subject by the be inferred from table 11 of Rinsky et ai. standard prevailing in that year and then (18) that the average duration of employ- summing these exposure years. Thin failure ment among men who had worked for at. is a major shortcoming of their risk assess- least five years was about 11yean. Presum- ment. However. this problem was corrected ably. 4.5, as opposed to 11. years of exposure in a more recent risk assessment based on a t such benzene levels wouid cause about a these data (see tieiow). fourfold higher cxrcw. Thc fi~mrcof 1'70 White c t ai. also did a risk assessment was obtained by considering that the over- ,.hased upon the result.sof the first report of all exrtw in rhc Pliofilin cnhnrt. wm 4Gn b rlw I h w riticlv. 1 liin r i y k t t w w t w t i t piv t w i t (i.c*.. tlw r a t v id h i k v t i i i i i iiiiiong yiclticd results similar to lhose ohtained the cohort was 5.6 times that of the general 3 from t h e Pliofilm data. As mentioned ear- population rate) and that the average dulier, the men in the Dow cohort probably ration of employment of leukcmiu CUPCS $Iere exposed to considerably lower levels was 3 3 years. The authors then assumed of benzene (cumulative exposure of about that this overail excess wouid increase `vb45 ppm-years) than were the men in the "smoothly' (presumably, linearly) from I Pliofilm cohort. Although there were two zero just after initial exposure to about leukemia deaths observed. compared with 2.400 per cent after 15 years Le., 460 x one expected in the Dow study. White et 45/8.51. The resulting age-specific excesses ai. did not use the resulting standardized were then applied to the age-specific leu- mortality ratio of 200: rather. a relative kemia rates. and the figure of 170 excess incidence rate of.3.X is used. This relative cases of leukemia per 1.000 men was oh- incidence rate is based upon the Occurrence tained. of three myelocytic leukemia cases among In our opinion, their second risk assess- the cohort compared with 0.A expected. k ment is wrong. The problem is evident in is emphasized that t h i s risk assessment is Iheir srntcment Lh;it "the overall relative nsk oC S A in the Rinsky study derives from However. their methodology can be upolied leukaemia cases who had an average of 8.5 m an occupatiunal jetting. years of.exposure." A relative risk does not The Group's risk assessment was based derive from leukemia cases: it is obtained upon the results of the Pliotilm study (17. from the comparative mortality experience 18). the Dow study (201, and Aksoy's study of exposed and unrxpused persons. T h e (29):For the Pliofilm study, they used an Juthors should have used the average em- overall dtandardized mortality ratio ul730, ployment duration oithe entire cohort (3.2 based upon nine observed leukemia cases years. our estimate based upon iniormation compared with 1.25 expected; The nine ob- in Rinsky et al. (18)) rather than that 01 served cases include two that were 'known the leukemia cases. Thus, the estimate of to exist" but were not mentioned on the ,, the excess aiter 45 years of exposure would death certificate. Since the expected num-+ be about 6,3(W per cent (Le., 460 X 45/33 ber of deaths is based only upon informa- rather than 2.400 per cent. If this correction tion on death certificates, the inclusion of is made. the result would be about three these two extra cases yields a spuriously iiinrs iu high. high standardized mortality ratio. This The authors judged that the Pliotilm co- group assumed that the Pliofilm cohort hort members had been exposed to between members had been e x p o d to between 10and 100ppm of benzene. They state that about 24 and 40 ppm of benzene. However, *assuming exposure was a t the upper end they erroneously assumed that these men of the range, then it is reasonable to pos- had been employed for 25 to 35 years, tulate that a working lifetime exposure to whereas their actual period of employment LOO ppm ofbenzene would be likely to revuk waa considerably shorter. If their risk as- in 140-170 cases of leukemia per LOO0 e r - sessment is applied u)a workplace exposure posed workem- However, it is unlikely that of 300 ppm-years, an estimate of about 15 these men were exposed constantly to as excess leukemia deaths per 1,OOO men is much as 100 ppm benzene, and it is cer- o b u i n d However, because of the errors tainly true that they were not exposed for discussed above, no confidence can be as long as 45 yean. Thus,this statement is placed in this estimate. not justified by the results of the Piiotilm The Carcinogen Assessment Croup also study. According to the White et al. risk based a risk assessment on the results 01 iit)wwiiient (57). 15 y e m i of cwpowrc to the Dow study. In doing so, they this timc ItNb ~ J ~ I I I IK'IWSIIC wt)ulil prtdtiw t w t w ~ r . : ~ ci)rmcLIycst.iiiiriiccl Llic rliirirt ~ I N I(11 w q h m - about 420and 1 . 5 0 excess leukemia deaths ment oC the cohort. Applying ~lieir risk per l.o(M) men. Recaw of the pkohlems assessment to 300 ppm-yean of benzene divcusved above, little confidence can be yields a11excess of 47 inyelcxytic 1eukcrltl.c placed in the risk assessment done by the deaths per 1O, OO men so exposed. This re- International Agency for Research on Can- sult is similar to that obtained by White rc cer, and their methodology is not applied al. I%). The Group also attempted LIJ use to an exposure situation of 300 ppm-years. the results of the study by hksoy (291III a The Carcinogen ,bses.sment Croup risk assu.s.srnmL risk assessment. However, it is difficult to interpret the result because OC the n i m y Iinii~ii~ionosf Aksoy's study anti we therc- The Carcinogen .dssessmenr Croup o t fore do not consider this risk assessnwnt the US Environmental Protection Agency meaningful. (61) has also done a benzene-leukemia risk assessment. The Group attempted KO esti- The Rinsky et ai. risk assessment mate the number ol'excess leukemia deaths This risk assessment is based upon rhe in the general population attributable to update of the Pliofilm cohort ( 191 and IScl11 exposure to benzene as an air pollutant. improvement over that done by White r'r -_ -__ .- **. --* -ma- *- a). 157) insairat as a cumulative measure of both a measure of the relative rate of dis- ben72nc! exlmsiire was ohtaind fnr each en.* among thc expnwd r o m p a d with Ihe ccihiirc nicniher. ttnexposcd nnd t Ircrcforc shoillti IK. ?cimil;tr. Rinsky CL 31. 119) repoft standardized It is apparent that the Rimky et d. model niortality n t i o s hccnrriing to four levels of overestimates the observed standardized cumulat ivc I)enzene exposure (less than 40 mortality ratios in the upper two exposure ppm-years. 40-200 ppm-years. 200-400 categories, especially in the highest. As an ppm-years, and mcLnt.er than 400 ppm- alternative risk assessment hn.don these years). The corresponding number of leu- data, we fitted a Poisson regression model kemia deaths and the standardized mortnl- using the four reported standardized mor- ity ratios (which have been divided by 100 tality ratios and the midpoint of their four so that thev can be compared with the odds cumulative exposure categories (62). Our ratios presented below) are 2 and 1.1; 2 and predicted standardized mormJity ratios are 3.2: 2 and 11.9: and 3 and 66, respectively. 1.2, 2.3. 13.6. and 6S, respectively. Our Thus, there is a strong positive relation model prnvides a conPiderahly hetter fit. to hetwecn srimrilntive hcntfint! c x p . s ~ i t cnnrl 1 Ire ctlvwwcfl si;i~iclrirclit~rtlilclrtctli(v rllt 11)s leukemia rnortulity in this study. than does t.hc model 0 1 Iiirisky e l ai. Our These investigators, however, did not. use predictsd nuinher of rxrcss leukemia the results of the cohort study to do the deaths for 1,000 men exposed to 10 ppm risk ;rsscssment. hilt. instcnd, did n ncrstrri I r n z r n c f'rw 3 1 vvnr?r lw~:i~ininn~i !3 1 ~ 9:!n 'Iviwv a - t b t a i roI IIIIV I t ) ~ t i t i ~ r l ~Ii-O* iIIlI rtdn ( w r yc-iifs I BIIWV~ 1 I I[)( I I I I. IIC I 1ixwt I rcgwsnii1Ii case) and used conditional logistic regres- model is 82. s i o n IO ciwivc aiti CX1H'"\itr-rl~(WItiX(. rc!liiLion between cumulative benzene exposure The Crump and ttllcn r i d assessment and leukemia mortality. Based upon their Cmmp and Allen (63)also have done a risk assessment. they would predict that benzene-leukemia risk assessment. Their 300 ppm-years of benzene exposure would risk assessment is based upon the results result in a n odds ratio (aieiative mortatity of the Pliofilm cohort, the Dow cohort, and me)of about 44, which we calculate m i d Wong's study ol chemical workers. yidd about 250 excess lifetime leukemia These investigators used two types of deaths among I ,OOO men exposed to 10ppm linear models for their risk assessment. The far 3c)years beginning at age 20 years. first,the a b i u t e risk model,amumes that In our opinion. lheir risk assessment the number of excess leukemia dentha at- shotrid have derived from the results of the tributable to a specific amount of benzene cohort study rather than from those of the exposure is constant at wery age (an addi- case-contmi studv. Presumahly, an esti- tive excess). T h e second, a relative risk mate of cumulative benzene exposure was mode!, assumes that the increase in leukc- available for ail cohort members. Thus. the mia mortality a t any age for a given level need to restrict the analysis to a subset of of benzene exposure is directly proportional the suhjects is undear. More importantly, to the baseline age-specific leukemia mor- if their riiocicl is ;Il)plicd CO Lhc dati~oh- tality rate (a multiplicative excess). They tained in the cohort study. the estimated also considered three measures of benzene ndds ratlos for the four categories of cu- dose: 1) lifetime cumulative exposure. 2) a mulative benzene exposure presented above weighted cumulative exposure which con- (using midpoints of exposure categories and siders recent benzene exposures ES most 480 ppm-years for the highest. open-ended relevant (exposures sustained between 2.5 categoryt are i.3. 4.5. 43.8 and 423. respec- and seven years before follow-up) and pro- tively. Although the interpretation of an vides progtessiveiy less weight to exposures odds ratio is not strictly comparable to that sustained in the more distant past, and 3) of a standardized mortality ratio. they are a window exposure method which essen- d y ignow all hnzene rxposurcr w- among the unexposed and therefore piace hined more than ISyears in the past. Their little confidence in it. relauve risk m d d used in conjunction wich h r n e uf the discrepancy between the risk I lifetime cumulative. exposure yielded the assessment results on the Pliofilm cohort highest risks. Since the other risk assess- reported by Rinsky et al. and Crump and ments discussed above used a rilative risk Allen apparently results from disagreement model with lifetime cumulative exposure as between them as to the levels of benzene to a measure or benzene dose, we repon here which these men were exposed. Crump and only these results from Crump and Allen's Allen's estimates of the benzene exposures repon. However, it is emphasized that their are generally higher (and therefore their risk assessment result based upon the ab- risk assessment results are lower) than solute risk model used in conjunction with those of Rinsky et ai., especially for erpo- the window exposure method yielded re- suns sustained between 1940 and 1948. sults about one-eighth as high as those However, Crump and Allen calculated that reponed here. This observation demon- if their exposure estimates ar6 decreased to strates that risk assessment results will levels more comparable with those of Rin- vary widely depending upon the choice of sky, their risk assessment results would the model and the measurement of benzene increa$e by about only 25 per cent. dose. Crurnp and Allen estimated that u)years Our risk assessment of exposure beginning at age 20 years to 10 We have used the method suggested by ppm benzene would cause 88 excess leuke- Enterline (64) for our risk assessment. An mia deaths per 1,OOO men so exposed. By estimate of I i f e b e excess leukemia deaths simple linear interpolation, we estimate attributable to benzene is obtained by di- that their risk assessment method applied \ for 30 years to LO ppm (beginningat age 20 yearst would yield about 68 excess leukemia daaths. These investigators also did a risk as- viding tbe difference between the observed and expected number of leukemia deaths by the total number of expected deaths (ail causes) in the C O ~ O K . The underlying assumption of this method is that the pro- sessment based solely on the Pliofim co- portional excess leukemia mortality ob- hort wing a relative risk m d e l with a served during the follow-up periodwill con- liieliiue cunruluirve c i 0 '~rh~cy did their tinue uiitil d l cohort members have died. own andysls of the Pliofilm cohort and If a cohort is followed until most of its were able to include additional years of members are deceased, the method will be follow-up. They report eight observed Icu- accurate. On the other hand, if a cohort hip kcmiu Jcutlls vc.mu.3 uiwut 3.0 erixqtcrt, heen h l l u w d lor only u smull fraction of yielding a mmiardized mortality ratio of its life expectancy, this risk assessment 268. Their risk assessment rcsult hased method must extrapolate the proportional upon the PLiofilm corlort is 63 excess leu- excess to future deaths and hence the result kemia deaths per 1,OOO men exposed to 400 is likely to be less valid and less precise. ppm-years of benzene, or about 48 for 300 In the latest report of the Pliofilm study ppm-years. They also did a risk assessment 1191,6.34 excess leukemia deaths were ob- based solely on Wong's study. From these served among the cohort (observed = 9, data, they calculate that exposure to 10 expected = 2.661. T h e total number of ex- ppm benzene beginning a t age 20 years and pected deaths was 331.6. Therefore, the continuing for 40 years would cause 121 number of excess leukemia deaths per 1O, OO excess leukemia deaths per 1,Ooo exposed exposed men is estimawd as men (orabout 94 for 300 ppm-years). Huwever, they point out that this excess IS due LOO0 X (6.31/331.6)or 19. Largely to a deticit of leukemia mortality To apply the method to an exposure situa- \ 1 J t i' tian of :!a)ppm-yenn. the benzene expo- m u l t in sures experienced by the Pliofihn workers must he considered and. hrthermore. it is nsmirnrtl I tilit ~:XITW Ic*cikc?miarncirinlitv is directly proportional to cumulative henzene dose. It can be inferred from table 2 X f300 ppm-ycnrsl4fi pprn-yen-) -= 46 per 1.000 excess leukemia denr.hs. .- nf their report that the average cumulative The retrospective follow-up study of re- henzene exposure ;irnong mcm1)crs of the finev workers hy Twi et. d.(2G) includctl Pliofilm cohort was about 69 ppm-years. estimates of benzene exposures. 'l%.w T h e excess number of leukemia deaths re- workers were typically exposed to less than sulting from 300 ppm-years is then esti- 1 ppm of benzene (median. 0.5 ppml. The mated as: average duration of employment was about (6.34/3:1l.G) seven ycnn. resulting in nn nvcrape cilrniilative benzene exposure of ahout 3.5 ppm- x (.?noppm-yendfi9 ppm-years) years. tf these refinery work& were sub- = R.3 pcr 1.OcH). jected to the same benzene-induced leukemin mortnlitv ns w w r t h e Pliofilrn workers. We also applicd Kiit.er1inc'a ~iic~licirI tli the Pliofilm cohort for follow-up through 1975 f 18) so that the result could be corn- pnrwl wit t i I hiit o T Whi1.c ct. nl. ( 5 7 ) . The 1.1i v i r t ivvrtiI I qt t i i11iri rtlixw I rw irt iil i t v rrrt i t i would be about 112. Therefore, the ohservation that there was no leukemia death ohsewed compnred with 0.42 expected does oi)ncrv.cd iitiiirIwr id Iccikcmiii tlc!iit Irn 11s (if that time was seven versus an expectation of 1.z!. 'l'llc* !.fdJd niiniiwv of cxpwt cd deaths was 161.3. We assumed, as did White et d..that these men had been exposed to between 50 and 83 ppm benzene rI I I I I i - o i r t riiclit-t Il i t e nwilirc iif I hi* d w v v r i s k assessments. Tsai's study is rimoly Loo&-'-. amnil nnd thc hcnrrnc expmires tnn lawp ,.%I for it to contributc Lo the kntanc-lcukemiri risk assessment. c- 1, The study by Wong (25) of chemic3 (say, 66 ppm). The average duration of workers also contains estimates of benzene employment for the entire Pliofilrn cohort exposures. There were 3,536 men %ontin- was about 3.2 years. The result is an excess uously' exposed to benzene in this study. of about 51 leukemia deaths per l.OO0 men Their average cumulative benzene exposure exposed to 300 ppm-years benzene. This was about 30 ppm-years. There were six result agrees reasonably well with that ob- observed leukemia deaths compared with tained by White e t ai. for long-term workers 4.4 expected (standardized mortality ratio only. I t should be mentioned that the cu- = 135) and the total numher of expected mulative benzene exposure level assumed deaths was 513. Therefore, the number of hy White et al. in their risk assessment and excess leukemia deaths resulting from ex- the level considered by us in this risk as- posure to 300 ppm-years is estimnted as: sessment are appreciably higher than the level of 69 ppm-years presented in the lat- (1.57/613) est report of the Pliofilm cohort (19). Enteriine'a risk assessment method also can be applied to the latest report of the x (300 ppm-years/30 ppm-years) = 26 per 1.000. Dnw cohort in which there were four leu- The result does not a m e well with that of kemia deaths observed versus 2.1 expected Crump and Allen (63).The discrepancy is (21). These men had an average cumulative in part related to the observation that there henzene exposure of about 46 ppm-years is no consistent dose-response relation be- and the total number of expected deaths tween leukemia mortality and the cumuia- was 2668.6. Thus. i t is estimated that 300 tive benzene dose in Wong's study and in pprn-vears of benzene exposure wouid part to the deficit of leukemia among the uirexl~iscdin his ..;tucfy. F I II ~hc.w ~ ; W ~ I I I S . The remilt rcuchd by Rinskv et i d . is w e M e v e t'hat Wling's study is not as considerably higher than rhe others. It is itiformaLive KO il risk assessment as are the diificult to understand why and, untonu- Pliotilm and Dow studies. nately,ye cannot directly attempt ta rep- S u m m a n i i risk assessments licate their case-control results. However. we did do two risk assessmenu based on Five risk assessments for benzene- the results of the cohort study from which induced leukeniia have been reviewed. T d d e 2 presents ii aumniury of the results of four ol` the risk dssessments based on the l'liotilm and Duw cohorts. along with their case-controi study derives. Our result using Poisson regression is $2 excess leukemia deaths per 1,000 men exposed LO 300 ppm-years. while our result based upon En- \ 1., our own estimares. Some ot'these investiyn- teriine's method is 83.Since the Rinsky et rors did not directly calculate the estimaces al. result does not agree with the others. displayed in table 2. but we extended including two independent risk assess- their methodoiogy to this particular expo- ments lours and that of Crump and Allent sure situi~ion. based upon the same cohort. we believe -Our own risk assessment results, those t h i r result is too high. of Crump and Allen (63).and those of An interpretation of these risk assess- White et al. (57) agree fairly well.' T h e ment results is that the Pliofilm study in- Carcinogen Assessment Croup estimate is dicates an appreciable excess leukemia risk -- --too low for the Pliofilm study because of an attributable to ben- zene and.t..hat,th.. e other ~ error regarding the duration of employment studies provide some support, or at least do of this cohort. as discussed. Their risk as- not contradict this.. H-o..-w. ever;.it must be ~~ sessment result based upon the Dow study, borne in mind that the at& awciies were however, agrees well with the other results. .- either very sma!l or s f l e d &it~qs- meth- Given the different methodologies and as- dological problems, so.that;d&te h e sunrptions applied by the various risk as- observation that they Seem to support the sesvment authors. the resuits, with the ex- results of a risk assessment based upon the ception of that of Rinsky ct al. (191, are Pliofilm study, little confidence can be reasonably cotisistent. placed in them. .Vrrnihvv q'h i ~ v t t t w1.11 TABLE 2 mrh-trk~*mctrclmrhv I.iNWI rrwkrm I - X ~ I U 1~1, Iii pptn hrn:c*ni* Il,r;M) , . , ~ r , . , * . ~ I I I I I I I I h. ~vI I~Y I ~ I I I Dr t r k I I S . W ~ . W # I I V I I ~ e ,.... ... .. -. --- - -4. I :to 3.6 42' Tliv rcwiillH of 1.hi - ~ i i e l e ~ t i ~ i i i I c i~~tiicrc. lic*s which we considered in our henzeneIciikrrnin risk nssessmcnt iirv tiislhvc*d in tddc :I. Tlic ovcriiil stunhrdizcd rnormliLy ratio from these four studies is 198. A weighted average (weighted according to the expected number of totaldeaths) of the cumulative benzene exposures sustained by the men in these cohorts is about 42 ppmyears. Thus, an overall estimate of the number of ex- leukemia deaths associated with 300 ppm-years of occupational exposure to benzene is obtained as: -(19 9.6)/1,273 x (300ppm-years/42 ppm-years) = 53 per 1.OOO. Using the lower and upper 9S per cent confidence limits of the overall standardized mortality ratio. a lower and upper bound for the number of excess leukemia deaths far 300 ppm-years of benzene exposure arc 10 and 11.7 per I.(Mo. respec- tiveiy. The estimates for 30 years of expo- sure beginninK a t age 20 years to the proposed new standard of 1 ppm benzene are one-tenth of these results. .ut r i i i t l r i r r l IS t t w t w t f i t c v i wit IcI r i i i iiiiirdiii;itt* excess of leukemia. *1. Iic c*l)ihnichgi:ic*litwnt iiri. r i i i I w t i m t w and leukemia supports the inference that benzene causes acute myelocytic leukemia. However, the availahie data are too sparse, or suffer other limitations, to substantiate the idea that this cau.sa1 association applies at low levels (Le., 1-10 ppm) of hnzene. Nonetheless. under the assumption that causation does apply a t such tow levels. a number of authors, including ourselves, have performed risk assessments using sim- ilar data but different methodologies. T h e assessments that we consiaer acceptable suggest that, among LO00 men exposed to benzene a t 10 ppm for a working lifetime of 30 years. there would occur about 50 excess deaths due to leukemia in addition to the baseline expectation of seven deaths. However, this estimate is speculative and whether or not enough confidence can be placed in it to justify a lower ocwpnt ional Iwnzene staiidnrd remains a decision for policy makers. SUMMARY Benzene is widely recognized as a leukemogen. and the Occupational Safety and Health Administration is currently attempting to limit exposure to it more strictfv. T h e proposed new regulation is a limit of a n eight-hour time-weighted average of 1 ppm in place of the current limit of 10 pprn. The fundamental rationaie for t h e change IS a perception that the current