Document qkaXkmME0zgo3YYQKo9Z3n5dq

. Leukemia (1995)9,693499 &ochton P r e i b AI rights reserved 08876924/95 $9 00 Exposure to occupational and environmental factors in myelodysplastic syndromes. Preliminary results of a case-control study *r* +A We performed a case-control study of occupational ana environmental risk factors In myelodysplastic syndromes (MDS) diagnosed at our institution, using the method of Siemiatycki. A control for each MDS case, matched for age, sex, and residence area was chosen. The questionnaire asked demographic data, medical history, and information on life-time environmental and occupational exposures. Occupational exposures were first assessed by job titles, then by evaluating exposure to a list of 70 chemicals, and the level and duration of exposure to those chemicals (exposure index). In the first 100 cases and controls analyzed, a significantly higher incidence of smokers or ex-smokers was seen in MDS cases (odds ratio, OR = 1.83, P = 0.03). A significant excess of MDS was found In male patients with jobs (or previous jobs) generally exposing to chemical compounds, including plant and machine operators and assemblers (odds ratio, OR = 3.73, P=O.O14) whereas, on the contrary, technicians and associate professionals were more often seen in controls (OR = 0.17, P = 0.002).In males, there was also a trend for more skilled agricultural workers and coal miners in MDS cases. In females, there was a non-significant trend for more professionals in controls. After adjusting for sex, age and smoking habits, significantly more frequent exposure to stone dusts (OR = 3.06, P=O.O11),and cereal dusts (OR = 2.27, P-0.04)was found. There was also a trend for higher incidence of exposure to exhaust gases and nitro-organic explosives. In addition, significantly higher exposure indices to petrol and diesel derivatives (P=O.O3) and to fertilizers (P=O.O03) were seen in MDS cases, as compared to controls. No significant difference in exposure to other chemicals was seen between MDS cases and controls. These preliminary results of our study, which is accruing more cases, suggest, as two previously published case-control studies of risk factors In MDS, that exposure to some chemlcals may be Involved in the pathogenesis of MDS. Keywords: myelodysplastic syndromes; occupational exposure; acute myeloid leukemia introduction Myelodysplastic syndromes (MDS) are clonal disorders o i hematopoietic stem cells, characterized by ineffective hemntopoiesis leading to blood cytopenia, and by a high incidence or progression to acute myeloid leukemia (AML).' Etiological factors of MDS remain poorly known. One of the reasons i s that MDS have only recently been well cham.terized2 and distinguished from aplasia and AML, especially in epidemiological studies or registries. A familial predibposition has been found in the rare cases of MDS occurring in childhood5 and, although to a lesser extent, in MDS occurring in young adults.b AML occurring after exposure to antineoplastic drugs (mainly alkylating agents) are preceded by n phase of MDS in the majority of c a ~ e s . L~ik, e~wise, a review of cases of AML secondary to ionizing irradiation (especially Correspondence: P Fenaux, Service des Malatlie, du Sang, CHU 1 , PIJW de Verdun, 59037 Lille, France Received 2 1 June 1994; accepted ti Decenilw 1994 in atomic bomb survivors)' and to benzene exposure".'()found that they were often preceded by a documented or suspected phase of MDS. Case-control studies or case reports have also incriminated exposure to several other compounds in the eti- ology of AML, including solvents other than benzene (xylene and toluene),'" ethylene oxide," pesticides and herbi- cides,iL,'-' chloramphenicol,'4 radon,15 and electromagnetic fields.' '.Ib An increased risk of dying from AML has also been observed in farmers and other agricultural w o r k e r ~ . 'H~owever, apart from alkylating agents, ionizing irradiation and benzene, a role for occupational or environmental exposure to other agents had not been demonstrated in the etiology ol MDS until recently."' Two recent case-control studies, which included about 60 and 50 patients, respectively, addressed this issue. Farrow et a/") found a higher incidence of exposure to ammonia, petrol and diesel fumes in MDS than in controls. Goldberg et aP" on the other hand, found more frequent exposure to pesticides in MDS cases than in controls. We performed a case-control study of occupational and environmental factors associated with MDS. Results of the first 100 patients analyzed are presented here. a% S CJ uP 2) m i2 93 (,q .a -11 22% 3 .W .-. -272 $c3is :c'sL) ::j ~ z:E + k- &J, g 'i.z=a=-! z0 0 CJ Patients and methods 3 2 ,$ 3in September 1991, a casesontrol study of occupational an@ 3environmental risk factors of MDS was started at our insti-?* ;1 J: tution. All cases of MDS (according to French-American-Brit-$ B Eish (FAB) diagnostic criteria)' diagnosed in the Department 0% p Hematology of the University Hospital of Lille were includecl;$ with the exception of MDS secondary to antineoplastic agents2 and patients who did not have the ability to answer the ques- tionnaire. Data of the first 100 patients, diagnosed between September 1991 and July 1993, are analyzed here. Overall, we used the same methodology as Farrow et id.''' This method, described by Siemiatycki" for identifying car- cinogens in an occupational environment, includes a control for each MDS case, matched for age ( 2 5 years) and sex. One of the major differences with the study of Farrow et a / was that the control for each MDS case was randomly chosen among the patients of the general practitioner of the MDS case rather than in outpatient clinics taking place in our hospital. Controls with cancers, blood or dermatological disorders, and those who did not have sufficient ability to answer the ques- tionnaire were excluded. A trained physician interviewed the cases and their appro- priate controls using a questionnaire. The questionnaire was similar to that used by Farrow et a/,'" translated into French. All interviews were carried out in the patient's (or control's) home. Confidential information included demographic data, lifetime residence, medical history including drugs, diagnostic X-ray procedures, radiotherapy, operations, past illnesses, smoking halits, and hobbies. Occupational history was first Occupationaland EnvironmentalRisk Factors in MDS Nisse et a/ 694 assessed by job title (according to the classification of the Table 1 Socio-economic characteristics of the MDS and control International Labour Office).2z Detailed analysis of each job populations was then made in order to estimate as precisely as possible exposure to a list of 70 chemicals whose list had been chosen MDS cases Controls P value based on literature data and on substances suspected of having causal links with leukemias. Finally, the level (Low level = 1: indirect exposure; Medium level = 2: direct contact; High level = 3: direct contact and inadapted conditions of use), fre- Sex Male Female 56 56 44 44 NS (xz test) quency and duration of exposure to a given substance was evaluated. An exposure index was then calculated (Index = Age (mean -c SD) 67.7 -r- 12.5 67 2 12.5 NS (Wilcoxon lest) (hours a day x days a year x number of years x level of exposure)/lO') for each substance. Exposure to potential toxic compounds during hobbies were also taken into account for the calculation or exposure indices. All questionnaires were blindly reviewed by the Medical Occupational Inspector of our region in order to reassess the job exposures over the occupational history according to the method of Siemia- Socio-economic status" Groups 0, 1, 2, 3 Groups 4, 5 Group 6 Group 7 Group 8, 9 Unemployed 14 23 12 24 22 5 27 23 3 24 17 6 NS (f test) tyck i. 2 1 The total bone marrow dose irradiation from diagnostic radiology was evaluated using the mean dose calculated by (cShlein et aP' for each type of radiological examination aAccordingto the International Labour Officemajor groups (ISCO88) and based on the last job held at the time of the study (dose x number of examinations)). 2.9 ? 1.6 in MDS cases, and 3 t 1.7 in controls (difference Statistical analysis was performed with SAS software. For not significant). job titles, the analysis was performed on the entire population, No documented familial history of hematological malig- and separately in males and females. Odds ratios (OR) were nancy, aplasia or MDS was found in patients and controls. calculated without adjustment, for the different jobs held over Past health was analyzed by classifying diseases in 14 speci- at least 6 months, those jobs being included in major groups alty groups, but none showed significant association with and subgroups according to the International Labour Office MDS. No differences between patients and controls were (ISCO 88).22Adjustment of OR for age and sex, using Mantel- Haenszel xz tests, showed equivalent OR, and are not shown. found for previous medical or surgical treatments. Past immunizations could not be adequately analyzed in many patients For the analysis of exposure to the 70 chemicals and other and controls, who had forgotten those data and/or lost substances, a logistic regression was used to adjust OR on age, adequate medical documents. Fifty-nine of the MDS cases sex and smoking habits. Finally, quantitative data (exposure were current smokers or ex-smokers, as compared to 44 of the indices) were compared using a non-parametric test controls, and the difference was significant ( P = 0.03, Table 2). (Wilcoxon test) as normality was not assumed. On the other hand, the risk of MDS was not higher in heavy smokers than in light smokers, as there was no clear dose response pattern, even after adjustment for age and sex, using Results a logistic regression ( P = 0.164). When past radiodiagnostic procedures were examined and Initial characteristics of the patient and control populations cumulative irradiation to the bone marrow calculated we found that, surprisingly, MDS patients had been submitted to a significantly lower cumulative dose than controls (13.4 t Median age of the patients was 70 years (range 31-87). Eighty patients were aged between 60 and 80, two were aged more than 80 and 18 less than 60. There were 56 males and 44 females. According to FAB classification, there were 28 cases of refractory anemia (RA), 10 cases of refractory anemia with ringed sideroblasts (RARS), 26 cases of refractory anemia with 14.8 mCy and 18.5 t 17.9, respectively, P = 0.04). No differences in the life-time hobbies of the patients and controls (including gardening, decorating, car maintenance, hobbies using paints and glues) were statistically significant, but slightly more controls (85%) than MDS patients (75%) had been involved in gardening. excess of blasts (RAEB), 12 cases of RAEB in transformation (RAEB-T), and 24 cases of chronic myelomonocytic leukemia (CMML). Median age of the control population was 69 years OccupationaI exposure (range 32-91) and controls included 56 males and 44 females (Table 1). As seen in Table 1, the socio-economic status was not sig- nificantly different in patients and controls, and remained so after adjustment for sex and age (Mantel-Haenszel x 2 : 3.02; P= 0.082). Analysis hy job titles: We first analyzed job titles, classified according to the International Labour Office Classification (ISCO 88),z2for major groups (Table 3) and for different jobs in those major groups. This was done in all cases and separately in males and females. The mean number of jobs held for at least 6 months was 1.93 ( t 1 . 3 ) in MDS patients, and 1.78 (?1.1) in controls (difference not significant, Wilcoxon Demographic data, medical history and environmental exposures Eighty-ninc of the patients and 89 of the controls had at least test). By analyzing males and females together, the compari- son of jobs held for at least 6 months showed an overall significant excess of MDS in plant and machine operators and x zassrnihlers (group 8 ) (odds ratio (OR) = 3.12, P = 0.012, lest) and, on the contrary a significant excess of technicians one child. The mean number of children in those persons was and associate professionals in controls ( O R = 0.28, P = 0.004). Table 2 Smoking habits Occupational and EnvironmentalRisk Factors in MDS Nisse et a/ MDS cases Controls Odds ratio (95% confidence interval) P value 1 Smokers 59 44 1.83 (1.04-3.21) 0.03 (xz test) (Current and ex-smokers) Non-smokers 41 56 0.55 (0.31-0.96) Pack-years 0 1-10 11-20 21-30 >30 41 56 0.55 (0.31-0.96) NS (x' test) 15 12 1.29 (0.57-2.93) 15 6 2.76 (1.06-7.24) 8 7 1.15 (0.4-3.32) 21 19 1 13 (0.56-2.27) Pack-years, number of packs per day x number of years r!",,.*=. e 695 The excess of MDS cases in group 8 was restricted to males controls with previous exposure to one of the 70 specific (OR: 3.73, P = 0.014). In males, an excess of MDS cases as chemicals and substances analyzed, an exposure index, taking compared to controls was seen in several categories of this into account the time of exposure during life, its intensity and group, including metal plant operators (two cases, one the route of exposure was calculated. Exposed MDS cases control), wood and paper plant operators (two cases, one were found to have a significantly higher exposure index to control), machine operators (three cases, one control), drivers petrol and diesel derivatives ( P = 0.03) and to fertilizers (four cases, two controls) but differences were not significant, ( P = 0.003) than exposed controls (Table 5). These differences probably because of the low figures in each category. By con- were related to differences in intensity rather than duration of trast, technicians and associate professionals (group 3) were exposure, as the mean duration of exposure was comparable significantly more represented in controls in males (OR:0.1 7, for all the compounds analyzed in MDS cases and controls. P = 0.002). The odds ratio (OR) for MDS cases were slightly increased in craftsmen (group 7) skilled agricultural workers (group 6) peop,le with elementary occupations (group 9) in Discussion males but differences with controls were not significant. Of note is that 13 of the MDS cases had been coal miners (a job To our knowledge, only two case-control studies investigating included in group 7), as compared to seven of the controls, the relationship between MDS and previous occupational or as coal mining was until recently a major economic activity environmental exposure to specific chemicals have been pub- in our region. The difference however, was not significant ( P lished.ly,Lo Our case-control study was based on the protocol = 0.16). established by the Cardiff group which performed one of those In females, very few MDS and controls belonged to groups studies, with few modifications.lY We used the same struc- 3 and 8 , which made comparison difficult in those groups. tured questionnaire and the job exposure analysis based on No differences were found between MDS cases and controls the Siemiatycki methodology.2' for group 7 (which included almost exclusively textile workers In case-control studies, the choice of controls is of major in females). There was a non-significant trend for more con- importance. Contrary to Farrow et d,"' we did not choose trols than MDS cases in females in group 2 (OR = 0.15, P = controls among outpatients referred to other departments of 0.1 1, Fisher's exact test). This group, in females, almost our hospital. The reason was due to differences in the British exclusively included teaching professionals. I and French health care systems. Indeed, there i s in France for most specialities (but not for Hematology, at least in our region), a large private sector which on average treats people Detailed analysis of exposures: We subsequently ana- with higher socio-economic status. The public hospital sector, lyzed in a detailed interview previous occupational and on the other hand, treats a higher proportion of people environmental exposure to a list of 70 substances. A compari- belonging to the working class, ie with a potentially higher son between the number of exposed MDS and controls was risk of occupational exposure to toxic compounds. Choosing studied when at least four persons in each group had been controls in other departments of our hospital could therefore exposed. Odds ratio were adjusted for age, sex, and smoking, have created a recruitment bias. The choice of controls among using a logistic regression. As seen in Table 4, previous the patients of the general practitioner of the MDS cases, exposure to stone dusts (OR = 3.06; P= 0.01 1 ) and cereal among other advantages, allowed matching for the area of dusts (OR = 2.27; P= 0.04) was significantly more frequent in residence. Cases and controls were also matched for age and I MDS cases than in controls. There was also a trend for more sex. The socio-economic status was not significantly different frequent exposure of patients to exhaust gases (OR = 2.19) in MDS cases and controls, supporting the absence of selec- and nitro-organic explosives (OR = 2.46) but the difference tion bias. On the other hand, although the interviewer was with controls was not significant. Exposure to stone dusts normally blind as to the patient-control status, many patients mainly concerned coal mining, whereas exposure to nitro- and controls revealed their status, and one cannot exclude organic explosives was only seen in that job. that this could have created some bias in the analysis. Still, the analysis was performed only on the exposures assessed by the occupational inspector who cotled each questionnaire (&an fificatioii of exposcires: Fir i IIy, ir i M13s patieri1s 1' ntl Idinclly to [lie status. Occupational and EnvironmentalRisk Factors in MDS Nisse el a/ 696 77- -N r.m 7-7 Occupationaland Environmental Risk Factorsin MDS Nise et al Table 4 Previous exposure to some of the 70 specific substances studied in the questionnaire in MDS patients and controls ?$ 697 I Substance 1 No. of exposed persons MDS cases Controls Odds ratio (95% confidence interval) Explosives 13 6 2.46 (0.84-7.14) i Petrol and diesel Oils and greases Coal Tar Exhaust gases 18 18 16 14 65 23 12 1 (0.47-2.15) 1.46(0.6-3.52) 1.08(0.3-3.85) 2.19 (0.95-5.06) Solvents Paint, varnishes I Glues, adhesive Sulfuric or hydrochloric acid I Ammonia fumes 28 18 10 6 10 27 19 8 7 6 1.08(0.54-2.17) 0.88 (0.4-1.9) 1.2 (0.43-3.32) 0.91(0.27-3.03) 1.57 (0.53-4.18) I Insecticides Pesticides Herbicides 13 13 11 13 18 23 0.89 (0.38--2.14) 0.66 (0.27-1.61) 0.64 (0.31-1.31) i Fertilizers Woodworm treatment 21 19 97 1.1(0.54-2.28) 1.26(0.43-3.67) Copper Metal dust I Asbestos Stone dust I Cotton dust 46 88 45 24 11 15 12 0.67 (0.17-2.68) 0.81 (0.28-2.37) 0.86 (0.2-3.6) 3.06 (1.28-7.32)" 1.45(0.61-3.47) I Cereal dust 24 12 2.27 (1.04-4.97)b 1 I Odds ratio are adjusted for age, sex, and smoking, using a logistic regression. j "P = 0.011. ' P = 0.04 I Table 5 Mean exposure indices in MDS cases and controls exposed to a given substance 1I Substance Mean exposure indices (range) P value (Wikoxon test) I MDS cases Controls 4 I I Explosives Petrol and diesel 18(0.2-88) 17 (0.2-37) 85 (0.5-250) 35 (0.02-190) NS 0.03 I Oils and greases 43 (0.2-195) 87 (4-334) NS I Coal Tar 61 (14-167) 50 (0.6-230) NS Exhaust gases 66 (4-250) 90 (23-231) NS !I Solvents 8(0.01-51) 8 (0.02-65) NS Paint, varnishes 29 (0.06-205) 17 (0.4-123) NS 1 Glues, adhesive 57 (0.1-435) 5 (0.12-25) NS Sulfuric or hydrochloric acid 5 (0.03-14) 3 (0.06-10) NS i Ammonia fumes 8 (0.3-40) 14 (0-38) NS Insecticides 2 (0.06-13) 3 (0.02-41) 0.03 I Pesticides 2 (0.01-13) 0.4(0.01-4) NS I Herbicides Fertilizers 2 (0.01-13) 4 (0.01-47) 0.3 (0.01-4) 1 (0.01-14) NS 0.003 ! Woodworm treatment 4 (0.1-25) 0 4(0.01-1) NS Copper 2Q(0.9-40) 23 (1.1-69) NS I Metal dust 17 (0.5-53) 25 (2.5-96) NS q Asbestos 34 (0.5-111) 15 (0.8-41) NS Stone dust 92 (0.7-275) 94 (1.6-222) NS I Cotton dust 31 (2.7-184) 57 (1.7-276) NS I Cereal dust 19(0.9-154) 14 (0.4-43) NS I I I Farrow et ally observed significantly more celibates among zations, and this did not allow us to confirm or not the higher 1 male patients than controls, a finding we could not evaluate incidence of previous poliomyelitis immunization found by because marital status was not included in our questionnaire. Farrow et all9 in controls. As these authors, we found no dif- I I We did not confirm, however, their finding that MDS patients ference in medical history and previous treatments in patients were more often childless than controls. Insufficient infor- and controls. We found a significantly higher incidence of i mation was obtained in patients and controls for past immuni- smokers and ex-smokers in patients than in controls, which m Occupational and EnvironmentalRisk Factors in MDS Nisse et a/ ~~ 698 had not been previously reported in MDS, to our knowledge. not differ, but that their exposure indices were significantly However, two case-control studies have shown a significantly higher in MDS cases. A history of exposure to pesticides was higher risk of AML in cigarette s m ~ k e r s . ~ ~ , ~ ~ also significantly more often found in MDS cases than in con- We found, unexpectedly, that controls had a higher calcu- trols by Goldberg et and in AML preceded by an MDS lated bone marrow irradiation by X-ray diagnostic procedures than MDS patients. An explanation to this difference could phase than in AML of acute onset in another report.29Insecticides and pesticides had also been previously incriminated in have been that patients chosen as controls for the study were often regular patients, who possibly had more frequent medi- leukemogenesis.12*1O3n the other hand, in our study, a larger number of MDS cases had been exposed to cereal dusts and cal surveillance (including X-ray procedures) than a general mean exposure to fertilizers was significantly higher in MDS population of the same age. cases, these findings being in agreement with the larger num- The odds ratio for job titles showed an excess of cases in jobs usually associated with exposure to chemicals. However, possibly owing to the small number of patients in each major ber of farmers in MDS. No excess of exposure to cereal dusts had previously been reported in MDS.19c20 Finally, Farrow et a / reported a significantly higher inci- group, no specific jobs could be incriminated. By contrast, jobs where less exposure to chemicals is generally observed dence of exposure to ammonia, a non-significant trend for chromium, lead and tin compounds and higher exposure indi- were more frequent in controls. A relatively high odds ratio was found in skilled agricultural workers but the difference with controls was not significant. Several previous studies have shown an increased risk of AML among farmers, and suggested that this could be the consequence of chemical exposures.' '8'' Evaluation of exposure to a list of 70 chemicals during life- time, including occupation time and hobbies, found significantly more frequent exposure to stone dusts and cereal dusts and a trend for more frequent exposure to exhaust gases in MDS patients, as compared to controls, after adjustment on sex, age, and smoking habits. The excess of exposure to exhaust gases in MDS cases i s in agreement with the findings of Farrow et all9 and those of Richardson in AML.I3 Contrary to the report of Farrow et a/,19 the number of MDS cases and controls previously exposed to petrol and diesel fumes or liquids was equivalent, but the mean exposure index was significantly more elevated in MDS cases. This stresses the interest of calculating the exposure index for each chemical, and suggests that the toxicity of some chemicals may occur above a certain threshold or is cumulative over time. A previous case control study had demonstrated a higher incidence of AML in petrol station attendants, and a potentiation of the leukemogenic effects of benzene by other petrol or vehicle exhaust ces to copper compounds in MDS patients, but we could not confirm these findings. In conclusion, these preliminary results suggest, as the reports of Farrow et all9 and Coldberg et aP" a possible link between exposure to some chemicals and MDS. In spite of preventive measures, benzene or other suspected substances including aromatic polycyclic hydrocarbons, contained in exhaust gases and petrol derivatives, could be incriminated in some cases. Fertilizers, insecticides and pesticides used by gardeners and/or agricultural workers, could also be implicated. Our findings of a higher incidence of MDS in smokers (and to a lesser extent in coal miners) will have to be confirmed, and the nature of the causative chemical(s) determined. Recent reports have suggested an increase in the incidence of MDS over the last few years',3o and, in a British Registry of Hematological Disorders thought to be associated with occupational hazards, MDS was the most frequent." if this increase does not only correspond to improved diagnosis of MDS in recent years, better identification of the chemicals possibly involved in the pathogenesis of MDS will have to be made, and preventive measures taken. Final results of this case-control analysis, which should include a total of 300 patients and 300 controls, should contribute to the answer to this question. components had been suggested.2hIn the report of Goldberg et a/,20 a trend for higher incidence of exposure to solvents (including benzene) was found in MDS patients, as compared Acknowledgements to controls, but the difference was not significant. Significantly more frequent exposure to stone dusts was also The authors are indebted to Dr R West and to the late Prof A found in MDS patients than in controls. Stone dusts were gen- Jacobs for their help throughout this study. Supported by the erally silica and exposure mainly involved coal mining, a major industrial activity in our region until recently. Coal Centre de Recherche en Sant6, Travail, Ergonomie (CERESTE), by the ComitC du Nord and ComitC du Val d'Oise of the Ligue miners were somewhat more frequent (although not significantly) in MDS cases than in controls. Coal mining contre le Cancer and by the Fondation de France (Fondation Weisbrem-Berenson). exposes not only to stone dusts, but also to exhaust fumes and to nitro-organic explosives, for which a non-significantly higher incidence of exposure was seen in MDS cases. Nitro- References organic explosives include nitroglycerine, ethylene glycol dinitrate and trinitrotoluene, and the two latter chemicals have been incriminated in the pathogenesis of leukemia and aplastic anemia, respectively." 272" Therefore the nature of the compounds which could be responsible for the excess of MDS in coal miners remains uncertain. In the present study, there was no increased exposure to herbicides, pesticides or insecticides in MDS cases, as compared to controls, both for the number of cases and the exposure index, and this did not confirm the results of Farrow ef <I/''' who found that the number of MDS patients and controls exposed to insecticides, herbicides, and pesticides did 1 Oscier D. Myelodysplastic syndromes. 6ailliPres Clin Haeinatol 1987; 1: 389-426. 2 Bennett JMrr a / . Proposals for the classification of the myelodysplastic syndromes. 6r 1 Haematol 1982; 51: 189-195. 3 Mole R. Ionizing radiations and human leukemia. In: Henderson E, Lister T (eds). 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