Document 7X5xEajGj2ZqMaB6X2zrYywV

Increased Risk of Developing Acute Leukemia After Employment as a Painter R. LINOQUIST. MD.' 8. NILSSON. 8S.t G. EKLUND. Pno. O O O W . DHc.t AND G. GAHRTON. MD' mse-control interview study of 125 adult patients with acute leukemia and 125 controls matched with respect to age ( 2 four years). sex, and residence MS carried out in c e n a l Swedea during the period from September 1980 to hlay 1983. Their history of orgnniC solvent exposure is described. A significant overrisk of developing acute leukemia was found when comparison between patients and controls revealed a ditTerence in the solvent exposure rate, which W.S significantly higher in patients than in controls, with an estimated odds ratio (OR) of 4.9.9546 CI (2.2 to 12.1). The most frequently exposed profession. painters. exhibit a relative risk of 13 (2.0 to 5%). These results suggest that an etiologic rehtionship exists between organic solvent exposure and tbe development of acute leukemia in man. Cancer 60:1378-1383.1987. 1N THE SEARCH FOR a causal relationship between the effect of chemical compounds on bone marrow cells and the development of leukemia, early studies on workers exposed to the aromatic solvent benzene revealed a possible relationship between benzene exposure - 4 myelotoxicity (Santesson 1897).' In 1928, Delore c . Borgomano' described the first case of acute leuke- ' .-.&ain heavily exposed workers and in 1932 Lignac-" found six leukemias and two lymphomas among 54 white mice exposed to benzene, whereas there was no leukemias among 1465 control mice. Later studies have confirmed that, in rodents, benzene inhalation produces myelogenous leukemia.' Although benzene may be the most important organic solvent associated with leukemia development,$occupa- tional exposure to organic solvents is usually complex. Therefore, results of epidemiological studies are usually based on information concerning the exposure to a mixturr of organic solvents and not to benzene a1one.A few such studies have been carried out and an increased risk ofdeveloping acute I ~ u k e m i aaf~te~r organic solvent exposure has been suggested. The sources of information were regi~ten.".~questionnaires to the next of kin' and case records supplemented by interviews of patients or of their relatives.' From the 'Dibisron of Cfinicrl Hrmaroloyy and Oncology. &panrnent of Llcdicinc. Huddinge Hospital and Karolinska Institutc. Huddinge: and the tDcpanment of Cancer Epidemioloqy. Radiumhommet. h r o l i n s l n Hospital, StocLholm. Sucdcn. Supponcd by the Swdish Work Environment Fund and Ihc Kamlintki Institute. 9-%- authors thank P r o f i r Lcnnon Erikwn for his comments on U+QL for reprints R. Lindquist. MD. Depnment of Medicine. Hu e, Hospital. S - I J I 86 tluddinge. Surden. Arrrptcd for publication March 13. 1987. The aim of the present study was to compare the exposure of organic solvents in patients with acute leukemia and in matched controls to evaluate the significance of such exposure in the etiology of acute leukemia Material and Methods Patients During the period from September 1980to May 1983, 125 patients with acute leukemia, who were treated in one of the five hospitals taking part in the collaborative treatment protocols of the Leukemia Group of Middle Sweden," were interviewed. Because of the way health care isorganized, the majority of patients with leuke:: ' in this e o n of Sweden are admitted to these hospi:; for diagnosis and treatment. There are no private clinics for leukemia treatment in Sweden, If a control had developed leukemia, he/she would have been treated in the same hospital asthe patient. Fourteen patients who were in too poor a condition to be interviewedor who had 100 poor a memory to m p i t u h t e information were excluded. One further patient refused to take part. An d m a t i v e to interviewing the patients is to interview the next of kin. The information obtained was n:'t comparable with the information obtained directly ! ' the patients and controls and could not be used in . i study. The patients were of run1 and urban origin. Seventy six were men and 49 wen women. The mean age was 49 years (range. I5 to 84 years). The mean age of the women was 51 years (range. 16 to 84 years) and of the men 48 ycus (range. 15 to 84 years). FAB cl;rs.ifimtion according to Bennett i'f uf.'I was mmed out with a slight mod leuke 17 p: I with acute Corti Or latior habit by di list, t k4. mntr ate t Couk -P Whe 137s .. PLAINTIFF'S EXHIBIT I No. 6 I379 modification." There were I4 patients with MI acute leukemia. 41 patients with M2. four patients with X13. I7 patients with M4, 1 I patients with Mj,24 patients with acute lymphocytic leukemia and four patients with acute undifferentiated leukemia. Con!rols One control per patient was obtained from the population register of the taxation authorities. where all inhabitants arc listed according to their addresses. district by district. Starting from the name of the patient in this list, the closest situated name of the same sex and age (24 yea^), as the patient was taken as a control. One control refused to take part, one was not able to cooperate because of a recent cerebral hemorrhage and one could not be found. Instead of these three, the next closest penons in the population registers were interviewed. When possible, the patient and the corresponding con- . trol were interviewed at about the same time. 1 Questionnaire and Gatheririg of Dara cCI -< The patients and controls were all interviewed in per- son by one of the authors (R.L.), according to a strictly standardized questionnaire. The questions were `ad- dressed to each subject in the same way and with the same words. Information was obtained concerning all occupations during the person's life-time, and of expo- sures t o specific chemicals. A list of professions. in ac- I. n e c n cordance with the principles of the Swedish Central Bureau of Statistics, was checked systematically with every subject to make it possible for everyone to recall former occupations. The questionnaire also contained questions about hobbies, tobacco use. use of medicines, exposure to x-rays. vaccines, former diseases, and living conditions. The educations and the professions of the .5- subjects were given in chronological order to describe c e the total life-span up to the interview. They were asked to describe working instructions and environmental exposure concerning inhalation. skin exposure and inges- 3 tion. They were also asked about different tasks within occupations and the way they performed the work. Dif- ferent activities within the profession of painten can easily be described and it is unlikely that the subjects did t not recall their activities Exposurc to organic solvents. paints and solvents. are uniformly used all over the country and wcll known by their users. The Swedish i National Board of Health and Safety has performed analyses of their content. As far as possible. quantitatively and qualitatiwly exact answers that could be di- rectly codcd for computer processing. were obtaincd. The chemical agents and the professions were listed and I coded for computing purposes. The questionnaire dealt t with professional and nonprofessional activities. Thcye Rticnts Espoud ESpo3ed Nones posed Nonesposed ~~ Referents Exposed Noncsposed Exposed Nones& ~~~ No.of oain a b C d is~lculatedJsthemiioofthenum~of discordant patients and controls. hvo parts are not combined in the analyses or in the presentation of the results, except i n table 6 concerning frequencies of skin exposure. Epideniinlogical arid Srarislical .\Iehds The analyses of the material have been performed by comparing bound patient-control pairs. Odds ratios (OR) were estimated (Table I ) and tested for the discordant pain according to Breslow and Day.""` Concordant pain. pain with solvent exposure of both patient and control. are disregarded. Multivariate analysis with logistic regression on matched data was also performed." Defiriirions Constant daily occupational exposure to paints and/ or organic solvents and/or organic solvent-containing gluc(s) during a defined period of time in life is termed professional exposure. Skin exposure is defined as skin cleaning with aromatic and aliphatic solvents. Thenpeutic x-ray is defined as lowdose gamma irradiation forjoint or back pain, e.g.. 2500 rad as surface dose four times as a courx of treatment. Petroleum products is defined ;1s fuel (diesel. gasoline, aircraft fuels) and its combustion products. Results Paituers Thirteen patients and one control had been painters. All painten reponed daily exposure to organic solvents by vapoun. A11 of them cleancd their lunds with solvents containing a inixturc of aromatic and alipllatic h>-drocarbons.The majority. 1 I painters mid thc control. were exposed bv direct skin application onc or more times daily. while two painters were e x p o d at l e ~ bly dircct skin application every wcek arid by other mmns of skin cleaning daily (Tablc 1). The estinrated odds ratio was 13 with a 95% contidencr intcrval (CI) (2.0 to 554). 'The median duntion of exposure for painters was I 6 y c ~ r s(range. I to 3 ycarr) and the .- f , I s TABLE2. Dam Gathcrcd hy Qucstionnairc Fmm h i n t e r Patimu Patient k control no. Agc*/xx Type of painters Occupation 31 thc time or diagnosis Patients I 2 3 4 5 6 7 85 9 105 11 12 13 Control I 41/F 72/M 32/M 2O/M 53/M 70/M I9/M S8/M S9/M 66/M 45/M 73/M 71/M 39/M Spray painter hinter + hobby utist painter Car painter Painter (metal machina) Painter. rubber bclory + paint Paminatenruf+achtoubrebry lnin painter Painter Boat painter Car painter Boat and building painter Boat painter S p y painter (anticomive wenu) W u m and cool asphalt painter Shoe factory (glue) Painter Car tester Railway. shunting yard worker hint manufactum Painter Painter Salesman Baker Pensioner Clerk Pensioner Pcndoner Car painter Assisant nurse ALL: acute lymphocytic leukemia: FAB: French-American-British classification of the acute leukemias. Median age. 58 yean. Solveni cavum WJt I n i c n d from cnd of cxpasurc to stan of diuuc$ Skin caposure 10 dvcnis Smoking duntion \'a0 ia 0 Daily 0 so 0 Daily 49 16 I Daily 17 I 2 hily 0 la 0 Daily 30 so 0 Daily 46 3 0 Daily 0 16 25 Daily 46 3 7 Weekly 43 10 28 Daily 0 4 22 Daily 19 5 6 Weekly 40 41 4 Daily 50 6 I2 Daily 0 t Median exposure, 16 ycars (range. 1 to 50 years). $ Median intcnal. 2 ycan (range, 0 to 28 years). 4 Ex@ IO therapeutic X-ray treatment to shouldm II TmoT (MI) A! L AU AU M2 M4 M4 ALL hl ! hll ALL M4 Mz MS -- median interval from the end of exposure to the development of disease was -po years (range 0 to 28 years). Five were o c c u p a t i o n a l E & i d at the time of leukemia diagnosis. Patients 8 and 10 had received x-ray treatment, Patient 8 twice, eight y e a n (right shoulder) and six years (left shoulder and back). before the diagnosis of leukemia and Patient 10. eight years before (one shoulder) diagnosis. Excluding the two individuals ex- posed to x-rays. O R = I 1 (P= 0.012. sign test). The shortest exposure to solvents ( 1 year) was seen in one young painter (Patient 4) who painted warm machines with anticorrosive agents and lacquers. Two painten (Patients 2 and 6)also painted as a hobby (artists)with a long duration of exposure prior to the diagnosis of leukemia. L Nonprofessional Painting T h e n was no oven11statistical difference between the nonprofessional painting activities of patients and controls. In fact 77 patients and 89 controls had been ex- posed to solvent-containing paints. The intensity of the nonprofessional exposure was ranked from single ocasions in life to periods of once a year, once a month. once a week and daily painting. There was no significant statistical difference between the patients and controlsas regards the low-grade exposure, but the more intense exposun. with frequencies of once a week to daily activity. was seen significantly more often among discordant pairs of patients compared to controls (P= 0.03) (Table 3). Exposure by inhalation of solventcontainingak From restoration of the patients' and controls' homes during single brief periods during the previous 5 years was no1 significantly different in the two groups. OrganicSolwnt EAponirc in DiflLwut Ocnipahns Organic solvenu am used as constituents of pain& glues and cleaning fluids in many different profcsi0M (Table 4). If excluded all patient-control pain Of painten. 26 patients and seven controls were occUP- tionally exposed to paints and/or solvents and/or due during a certain periodoflife, disregardingfour . "-1. 60 -- r y p c or Icukcmia -(FAB) ALL ALL ALL M2 M4 M4 ALL MI M2 ALL .u4 M2 c- 2 ocanonth. *ificant t rols as . n tense 3ctiv.xdant 0.03) * from ,Juring .is not :s :aints. sions S glues PO4 No. 6 -R I S K OF ACWTE LEUKEMIA AFTER PAINT EXPOSURE Lindqiiisr el a!. 1381 TABLE3. Frequency o f Nonprofeskwd Painting Activities Amonn Paticnu and Conuob Frequency of activity No.o f discordant painof patients No. o f dimrdaat paisof controls P value o f cornparison between discordant pain of patients and controls Daily Weekly Monthly Yurly Once Never exposed 3 6 6 21 23 35 ~ ~~~ ~~ NS: not signifimnt. One-tailed significance (at. II 1 6 24 39 23 0.03. NS NS NS NS NS concordant pairs. The ratio 26 to 7 is highly significant (P= 0.00 13)when tested for the equality of proportions in matched samples (by sign test, 1947)." The OR ofthe overall exposure to solvents is estimated to be 3.7, with the 95% CI Iimit calculated by binomial distribution to be 1.6 to 10.I (Table 5). The median time of exposure of discordant patients was longer than that of discordant controls (nine years compared to four years). The median time from cessation of exposure to the develop ment of leukemia was I5 years (range, 0 to 40 yean). Median time from cessation of exposureto interview for controls was 16 years (range 0 to 24). -Skin Expo-s_ur_e to Or-g-ani--cSolvenls - . -The distribution of patients and controls regarding the frequency of&n cleaning with organic s o l v e s h o w that there was no disc in low frequency exposure, but daily exposure was noted in 18 patients and six controls (Table 6): They were using white spirit 17% to 22% aromatic hydrocarbons) and/or gasoline with a high aliphatic hydrocarbon content &d about38 aromatic hydrocarbns. The aromatic hydrocarbon fraction is composed of xylene. toluene, trimethylbenzene, and benzene. I6 TABU4. Diwibution of Occupations Exposed to Organic Solvenu Acrording to the l n t e n i m Occupation No. of discordant patient. NO. or discordant controls Painter R u b industry worker phvnuccuticri ni dw worker Upholsterer car WUL duna Printing worker Dry cleaner Car repairman WOOdWOfker Shoe raaory vrorlrcr Book bider Textile printing worker Trainbus wagon +rmm Shipyard worker Sign painter New building & a n a Isolation worker Metal indusuy printing worker Dispensing chemist NU= 13 I I I I I I 3 4 2 I I 2 I 1 I I I 1 1 I 0 0 I 0 I 2 0 0 I 0 0 I 0 0 0 1 0 0 0 The exposure to ether anesthesia was the same in patients and controls (58 patients exposed compared with 57 controls; discordant pairs, 27 patients and 26 controls). The solvent-exposed patients were not significantly more often exposed to this form of anesthesia than other patients. Smoking Habiu Thirty-one percent of the painters had not been smokers. Considering all patients and controls, the smoking habits were similar (Table 7). Forty-two percent of all the patients and 48% of the controls had not been smokers. Neither differences between discordant pairs nor strata of patients and controls proved to k of statistical significance when the duration of smoking, TABLE 5. L~posurcto Organic Solvenu' Rtienu ContmCr l i m e from end Time from end Time of exposure of exposure to Time o f expcuurc ofexposurc to ~upaoonnl (VI diagnosu (yr) (Yr) interview (yr) organic solwnt exposurc No. Median Range McdLn L n g e No. Median Rang Median Range P OR (CI) Painten Professions aher thanpaintas Toul 13 26 39 16 1-50 2 0-28 I 9 O.l-60 10 0 . 1 4 I5 0-40 7Mo 7 a 6 4 1.540 5 1-. 12 0.002 13 (2-554) 16 0-24 0.001 3.7(1.610.1) I4 0-24 <0.001 4.9(22-121) f- I 1382 TABLE 6. Frcqucncy Skin Expowm of Pmlcssonals and Nonpml'cssionals to Orpntc Solwnu Frequency or erpnurc NO. or paticnu ~0.d conids P OR CI (tnnomid diunhuiion, Daily Weekly Some orruionJyear Sin& -ons/yar Sin& o~csuons Nrmaporcd I8 12 34 I? 18 31 b co.05 3-o: (1.,,4!"' I I NS 41 NS IO NS 20 NS 17 NS OR:ai& mio: CI: confidence inieml: Ns:nonsipificant. number of cigarettes consumed, pipe smoking. or snuff use were tested. Mirhivariale Atialysis Multivariate analysis expressed as logistic regression on matched data showed no interaction between organic solvent exposure, smoking habits, x-ray exposure and petroleum products (Table 8). FAB Classes The distribution of French-American-British classification of the acute leukemias (FAB) clues''." among patients exposed to organic solvent-containing compounds showed that no single patient had the diagnosis +of promyelocytic leukemia (M3)or erythroleukemia (M6)(Table 9). Leukemias of the MI M2 types were found significantly more seldom among solvent- exposed than among non-exposed patients (P= 0.01, chi-square test) and the M4M5 leukemias were found significantly more often among exposed patients (P= 0.02). Discussion Our results indicate that regular exposure to solvents is associated with an increased risk of developing acute leukemia. Heavily exposed persons, such as painters. exhibit the greatest O R ( 13). while solvent-exposed per- sons other than painters have an excess risk of 3.7 when compared with nonexposed personr Multivariate analysis showed no interaction between solvent exposure, to- TARLE 7. Tobcco Use (During any Period of Life) by Patients and Conirols. Catcgory NO. or paticnu No. of controls Ciprrcite smoken P i p smokers Snuffwkcn Nonsmoken 63 20 18 52 62 10 19 60 - *The same individual may haw consumed 10hK.Co in diffmnt rmr Variable dP I'hmpcuiic x-n! 1.51 oma Organic scrlrcnis I.Ytl 4.00I Petroleum pmducts IA 2 0.020 8: rcgrrssionrir&cni.i' Multivariate m d y s i s using logistic n-gnuion on mlchL-d&u showed no i n t m ~ 7 i o nkiwccn cxposurr to thcnpcutic x-rj\ menL solvcnir or psrolcum prducts. All vanahla were rod& I!- 1: 0, not exposed: I. cx:rFmcd. hnolhcr considered (NS)m5aMe u% hJmuse. bacco use. therapeutic x-ray exposure, or petroleum products. The solvents uscd occupationally by painters conga of mixtures of aromatic and aliphatic hydroc;l&nel6 Although knowIedge of the toxic effects of benzene h a resulted in its prohibition in Sweden as a pure solvent, it is impossible to prevent complete prohibition. It :>ften occurs as an impurity in other solvents, in paints and is used as an additive in gasoline. Benzene is metabolized to benzene epoxide, a highly reactive compound, which in turn is metabolized to phenol, which is oxidized to alkylating This could be one mechanism for cellular damage. For exam- ple, Snyder m uf. have shown that a benzene metabolite is bound to bone marrow cells.'9 and %pya er ai. have noted stemcell injury leading to diminished cell replication and other cellular abnormalities in it! i 3 r O liquid bone marrow cell cultures exposed to benzene.= Toluene (methylbenzene) and xylene (dimethylbcn- zene) can be metabolized by the same pathway but to a lesser extent, because they are also metabolized on methyl groups into carboxyl acids, which can be conju- gated and excreted.*' Human leukemia and aplasia of the bone marrow following inhalation of Mpor from toluene-containing glue was' observed in youngsten as- sembling model building set~."-~I't is therefore proba- TABLE 9. Distribuiion of FAB Classes Among Patients E . w d Organic Sdvenu and Nonexpoxd PJtima' Nompovd Exposcd AllplknU MI-MI M3 M4+MS ALL AU1. No. Percent No. Pcrccnt ~~~~~ 42 i a 12 22 4 loo 0 0 10 5 1 19 49 13 52 12 48 3 loo 0 0 82 66 43 34 No. ~~ w 4 39 Y 3 I3 pt 0.0 I 036 0.01 0.11 0.55 "01. 60 i -- .r.hcd data .-ray t r u t Jrdo-t:O. *lewas to- *troleu m s consist irbons.'6 iene ha> dvent, it It often ts and is a highly .lized to 5.11 niS (-- 7 - .e '.a ai. .bed cell in vitro izeneS hylbenSut to a ized on :conju:lasia of ir from S k K aS- -- proba- ` posed10 -.5 Pt 0.0 I 0.36 0.02 0.1: 0.51; CXd No. 6 RISK OF ACUTE LEUKEMIA AFTER PAINT EXPOSURE Lindqrtisr el a/. I383 ble that the metabolism lo epoxides and phenols is suf- ficient for the induction of bone marrow cell damage and leukemia. Cytogenetic analyses of human lymphocytes have in- dicated mutagenic propenies of and tri- chloroethylene.*' Also, increased chromatid exchange and chromatid breakages were found in laboratory and printing works employm who were exposed to solvents as compared to nonexposed controls."' Chromosome breakages are increased in blood lymphocytes of plastic factory workers e x p o d to styrene." Thus, a substantial amount of data shows that many organic solvents and their metabolites are mutagenic. This may explain why exposure to them increases the risk of developing leuke- mia. However, the mechanism behind the mutagenic action is complex, and there is little knowledge about the relative risk of each specific organic solvent or its metabolite/s. For painters, the median time of solvent exposure was 16 yean (range, 1 to 50 years), but the median interval from the end of exposure to onset of disease was two ycars (range, 0 to 28 years). Five painters acquired leu- kemia while still engaged in professional activity after 18, 18, 50, 50, and 3 years of exposure, respectively. Thus,the results suggest that there is an excess risk aAer a short period of exposure. Furthermore, we find that onset of the disease can occur in association with the exposure aswell as aftercessationofexposuic. The same result was obtained by Rinsky el ul. who studied leuke- mia in benzene workers." Organic solvent exposure has been associated with the development of both myelocytic and lymphocytic leu- kemias and lymphomas. In a report from Turkey'3 on 34 patients chronically exposed to benzene, Aksoy el ul. found both myelocytic and lymphocytic leukemias. McMichael et af.reported a sevenfold increase in the relative risk of developing acute lymphocytic leukemia in workers exposed to solvents? Two casccontrol stud- ies, by Hardell ef uLWand by Olson and show an increased risk of developing lymphoma after expo- sure to organic solvents. This was also found by Ohlin a n d A h l b ~ m 'c~oncerning cancer mortality among Swedish chemists exposed to solvents. Aksoy er ul? re- ported an incidence of leukemia of 13.5 per 100,OOO individuals with chronic exposure to benzene, com- p m d to the overall incidence of six per IOO,OOO,a sig- nificantly greater risk (P< 0.001). when exposed. The OR was 13.5/6 = 2.25. When estimating the OR of malignant lymphoma Hardell er d." found that in pa- tients with high-grade exposure to organic solvents, the OR was 1 1.1, 95% CI (1.9 to 1 I .4). The high-grade ex- posedgroup is comparable with the group of painters in our study, whose O R = 13(1.95 to 554). The results arc consistent. suggesting the estimation of the ovemsk to be in the lower span of the confidence interval. A comparison of the distribution of F A B classes (Table 9) among our patients exposed to organic SOIvents and nonexposed persons indicates that the FAB M4 and M5 subtypes of leukemias are more frequently -observed among exposed persons (P= 0.02, chi-square test) and FAB MI and M2 subtypes lcss frequently ( p 0.00 I, chi-square test). A Swedish death certificate cohon study of 416 paintindustry workers exposed to organic solvents, has been pmented by Lundberg et af." Cause-specific mortality was studied. Among 96 workers who died,three died of multiple myeloma, compared with 0.6 expected deaths. Five deaths of disease of the lymphatic and hematopoietic systems were observed compared to 2.4 expected deaths with an estimated OR of 2.12, 95% CI (0.68 to 4.96). The alkylating agents of metabolized aromatic com- pounds, such as epoxids, have an effect most probably consistent with cancer initiator, inducing DNA damage and turning the normal cell into a malignant cell. An initiating agent, if sufficiently strong, can theoretically express its capacity after a single exposure, thus explaining the occunrnce of leukemia in individuals with a short exposure time. The same DNAdamaging p r o p erty can also induce chromosome abnormalities which may predispose second event/hit to induct the malignancy. The mechanisms of bone marrow cardnogenesisgiving rise to acute leukemias is still obscure. In the case of alkylating agents, the situation seems to have much in common with the expenmental model for rat liver carcinogenesis, called the resistant hepatocyte model.M39 In this model, initiated cells are generated by the use of mutagens in the presence of cell proliferation. The initiated cells are selectively favored in their proliferation during the promotion phase because they an resistant to the mitoinhibitory effect of the promotor." This differential sensitivity concentrates the mitogenic power to the initiated cells, permitting them to clonally expand to focal cell populations with a high rate of basal cell proliferation and a high risk of rare mutation-like events that pushes them another step forward in the process of cancer development. In the bone marrow, alkylaton form DNA adducts that probably give rise to mutation- like events in rare cells. Alkylaton have also been shown to be mitoinhibiton for bone marrow stem cells," de- pressing the production of leukocyte and thrombocytes. Thus, it is possible for mistant cells to develop (mutation/initiation) and the prerequisites (organic solvents), are at hand matching the analogy with experimental models obviour In experimental carcinogenesis and in other examples of human cancer development, the PfO- cess is slow and takesa considerable part of the lifcspan to reach the terminal stage ofmalignant d o r m a t i o n . During that time, the subject does not have to be to the CASCER September 15 1987 Vol. 60 carcmogen exposure constantly. In the optimized experimental liver models, dependent of both initiation events and promotion. initistion is a onedose event and promotive treatment is performed for 2 weeks. Camnomas in this model are Seen 10 months affcr initiation. Potent carcinogen exposute in young animals with a high rate of liver cell proliferation results in hepatoma development within 2 to 3 months. Our mults point to a greatly increased risk of deveioping acute leukemia after exposurc to organicsolvents Furthermore. noxious effects of t h e e compounds on the kidneys,'* the nervous ~ystern'a~nd the liver" have been reported. Today, occupational exposure to organic solvents is widespread and complex. and it is important that further efforts be made to minimize such exposure. REFERENCES 1. CG !hntesson. Ueber chronische VergiRungen mit Steinkohlea- enrheer benzene vier todesfdla Arch H.vg Bed 1897;3 1:336-376. 2, Delorc P. Borgomano C. Lcu&mie aigue en course de I'intoxiu- cion benzinique sur I'origine toxiquc de ccrtaines kudmies aigua et kur dations avcc laanemics gramJ Med Lwn 1928; 9:227. 3. Lignac GOE. Die Benzol Leukemia ki Menschen and weissen h u s e n . Hut IVuchenschr 1932; 12109-1 10. 4. Snyder C.4. Goldstein BO, Sellakumar AR. 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