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Cancer Causes and Control (2005) 16:939953 DOI 10.1007/s10552-005-2301-3 Springer 2005 Occupational exposures and haematological malignancies: overview on human recent data Alexis Descatha1,*, Arash Jenabian2, Franc oise Conso3 & Jacques Ameille1 1Unite de pathologie professionnelle et de sante au travail, Ho^pital R. Poincare, AP-HP, 92380, Garches, France; 2Service de cancerologie medicale, Ho^pital Europeen Georges Pompidou, AP-HP, 75015, Paris, France; 3Service de pathologie professionnelle, Ho^pital Cochin, AP-HP, 75014, Paris, France Received 25 October 2004; accepted in revised form 15 February 2005 Key words: leukaemia, lymphoma, multiple myeloma, myelodysplastic syndrome, occupational disease. Abstract Objective: Occupational causes of haematological malignancies are relatively uncommon, under-studied and underidentified. They are also often unrecognized by clinicians. This review summarizes the principal epidemiologic studies on this topic. Methods: We analyzed the recent relevant human data found in the Medline, the Pascal and the BDSP databases. Results: Benzene and ionizing radiation are the only agents conclusively demonstrated to be carcinogenic to the haematopoietic system. In particular, both exposures are strongly associated with acute myeloid leukaemia. Low doses of both may also be related to myeloid malignancies. Infectious agents and pesticides are also thought to induce lymphoproliferative cancers. Some studies show an association between haematological malignancies and low-frequency electromagnetic fields and organic solvents. All of these suspected occupational causes must be confirmed by further studies. Conclusions: Better knowledge and understanding of occupational causes of haematological malignancies are necessary to improve their prevention and compensation. Introduction Historically, one of the earliest examples of a haematological malignancy thought to have an occupational cause is the blood cancer that probably killed Marie Curie: despite some diagnostic confusion, her cause of death was most likely due to occupational exposure to ionizing radiation exposure [1]. Although the known occupational causes of malignant blood diseases were once relatively rare, chemical and physical environmental hazards are thought to explain the increasing incidence of these diseases, especially lymphomas, over the past three decades * Address correspondence to: Alexis Descatha, Unite de pathologie professionnelle et de sante au travail, Ho^ pital R. Poincare , AP-HP 92380 Garches, France. Ph.: +33-1-47-10-77-54; Fax: +33-1-47-10-7768; E-mail: alexis.descatha@rpc.aphp.fr [2]. Moreover, the risk of leukaemia attributable to occupational factors has been estimated at 10% in the USA [3, 4] and 510% in Europe [3, 4]: occupational causes would thus account for 111224 incident cases of leukaemia per year in France, although only 20 leukaemia patients received disability compensation for an occupational disease in the year 2000. These figures indicate the extent to which the occupational causes of these diseases are under-diagnosed, in part because physicians often do not recognize their occupational factors. Furthermore, many occupational causes of these diseases are simply unidentified. Benzene and ionizing radiation are the only agents conclusively proven to be carcinogenic to the haematopoietic system, although other occupational exposures are suspected of involvement in these diseases [1, 5, 6]. The purpose of this paper was to review the available epidemiologic data about occupational sources of haematological malignancies. 940 A. Descatha et al. Material and methods We searched for relevant publications from 1992 through 2004 in three databases: the Medline database, the Pascal database (developed by the French national centre for scientific research, CNRS) and the BDSP database (developed by the French national school of public health, ENSP). We used the keywords leukaemia, lymphoma, Hodgkin's disease, multiple myeloma, and myelodysplastic syndromes, together with occupational, work, and occupational disease. To be exhaustive, we also checked cohort studies on major occupational exposures that have been linked to haematological malignancies. For this search, we used the following keywords `occupational' AND `cancer' AND (`benzene' or `petrochemical' or `gasoline' or `nuclear industry' or `ionizing radiation' or `pesticide' or `farmer' or `butcher' or `meatpacker' or `slaughterhouse' or `abattoir' or `virus' or `microbe' or `organic solvent' or `beautician' or `hair dye' or `diesel exhaust' or `embalmer' or `anatomist' or `pathologist' or `formaldehyde' or `health worker' or `antineoplastic'). We looked only at published data for humans and rejected studies with imprecise descriptions of exposure or diagnosis. Toxicological studies, particularly studies of biochemical pathways, were not included. Case reports were also excluded, but well-documented reviews were included, in part to ensure that our review took into account studies published before 1992. We analyzed 153 papers: 71 cohort studies, 46 casecontrol studies, and 36 meta-analyses or critical reviews. They came from journals in the fields of occupational health (65%), epidemiology (12%), haematology and oncology (14%), and other fields (toxicology or general, for the remaining 9%). We report the results according to strength of evidence and agent. Tables 110 summarize the principal results of selected studies according to disease. Results Demonstrated occupational causes A causal relation with leukaemia, especially acute myeloid leukaemia (AML), has been demonstrated according to the Bradford Hill criteria (strength of association, consistency, specificity, temporality, dose-response relationship, coherence and analogy) for only two agents: benzene and ionizing radiation [57]. Ionizing radiation Ionizing radiation has been classified as a certain carcinogenic hazard (group 1) by the International Agency for Research on Cancer (IARC) [5]. AML. The causal relation between ionizing radiation and haematological malignancies was first demonstrated during the follow-up of the Nagasaki and Hiroshima atomic-bomb survivors by their high incidence of AML [6, 7]. In the workplace, a retrospective cohort study of nuclear workers found an elevated mortality rate from leukaemia (Table 1), significant only for high exposure (cumulative dose higher than 200 mSv) and considering all haematological malignancies, with a rate ratio estimated at 15.65 (95% CI: 3.3373.50) [8]. Low doses of ionizing radiation and leukaemia. The United Nations Scientific Committee on Effects of Atomic Radiations (UNSCEAR) reported in 2000 that levels of occupational radiation exposure today are approximately half of what they were in earlier decades. The average annual effective dose in the 1990s has been estimated at 15 mSv [7]. Some studies of nuclear and medical workers have examined in more detail the relation between exposure to low doses of ionizing radiation (<5 mSv/year) and leukaemia [813]. Pooling mortality data from seven cohort studies covering 96,673 nuclear workers, the IARC study group found a significant excess relative risk of leukaemia [excluding chronic lymphoid leukaemia (CLL)] associated with exposure to ionizing radiation (Table 1) [9]. The mean duration of exposure was 36 years and 80% of the study population had a cumulative exposure less than 50 mSv. Other types of leukaemia and myelodysplastic syndromes. A cohort study of workers who participated in the United Kingdom's atmospheric weapons tests and experimental program found them to have a significantly increased relative risk of leukaemia (CLL excluded) [14]. The UNSCEAR report in 2000 also noted associations between exposure to ionizing radiation and leukaemia, except for T-cell leukaemia and CLL [7]. A casecontrol study showed an association between occupational exposure to ionizing radiation and myelodysplastic syndromes (Table 4) [15]. Malignant B-cell lymphoproliferative disorders. No epidemiological data support a causal relation between occupational exposure to ionizing radiation and nonHodgkin lymphoma (NHL) or Hodgkin disease (Tables 6 and 7) [7, 16]. A casecontrol study showed an excess risk of multiple myeloma (MM) among older nuclear facility workers exposed to low levels of ionizing radiation: the odds ratio reached 5.15 in the group with thehighest exposure at the age of 45 and older (cumulative dose of 100 mSv or more) [17]. A cohort study Occupational causes of haematological malignancies 941 Table 1. Epidemiologic surveys of occupational leukaemia, all types, not specified References Study design Exposure or job Risk estimation CI 95% Guenel 2002 [23] Seniori 2003 [27] Rinsky 2002 [26] Rinsky 2002 [26] Rinsky 2002 [26] Wong 1999 [33] Huebner 2000 [52] Wong 2001 [28] Sathiakumar 1995 [30] Gun 2004 [144] Hunting 1995 [25] Wong 1999 [33] Cohort Benzene Cohort Benzene (>200 ppm years) Cohort Benzene (between 40 and 200 ppm years) Cohort Benzene (between 200 and 400 ppm years) Cohort Benzene (>400 ppm years) Nested casecontrol Gasoline (35% benzene) Cohort Petrochemical industry Cohort Petrochemical industry Casecontrol Petrochemical industry Cohort Petrochemical industry Cohort Vehicle mechanics (benzene exposure) Nested casecontrol Gasoline (35% benzene) OR = 1.2a,b SMR = 5.1a,b SMR = 3.21b SMR = 5.55b SMR = 23.96a,b SMR = 0.80 SIR = 1.29 SMR = 1.37 OR = 2.0b SIR = 1.39 SMR = 9.26a SMR = 0.80 1.01.5 1.413.0 0.868.89 0.6224.08 4.8278.51 0.561.07 0.752.07 0.961.88 0.974.2 0.912.02 1.1233.43 0.561.07 Blair 1998 [46] Cohort Gustavsson 1999 [145] Cohort Steenland 2004 [118] Cohort Coggon 2004 [117] Cohort Eisen 2001 [146] Cohort Divine 2001 [107] Cohort Santos-Burgoa 1992 [111] Casecontrol Santos-Burgoa 1992 [111] Casecontrol Hauptmann 2003 [125] Cohort Coggon 2003 [127] Cohort IARC 1994 [9] Ritz 1999 [8] Sont 2001 [16] Muirhead 2003 [14] Meta-analysis Cohort Cohort Cohort Trichloroethylene Chemical industry Ethylene oxide Ethylene oxide (chemical and hospital) Automobile industry (metalworking fluids) Butadiene Butadiene Styrene Formaldehyde (peak levels >4 ppm) Formaldehyde Ionizing radiation (low doses) Ionizing radiation Ionizing radiation Ionizing radiation RR = 0.6 SIR = 2.24 SMR = 0.99 SMR = 1.08 SMR = 1.34a SMR = 1.29 OR = 9.36a OR = 3.13 RR = 3.46a,c SMR = 0.91 Meta ERR = 2.2 (by Sv)a RR = 1.60 ERR = 5.4 (by Sv)a RR = 1.83a,d 0.31.2 0.466.54 0.711.36 0.352.51 1.141.58 0.772.04 2.0522.9 0.8411.2 1.279.43 0.621.29 0.15.7f 0.952.52 0.220.0f 1.152.93f Kheifets 1999 [61] Harrington 2001 [62] Hakansson 2002 [63] Hakansson 2002 [63] Morgan 2000 [64] Savitz 2000 [147] Meta-analysis Electromagnetic fields RR = 1.09 (by 10 lT years) 0.981.21 Cohort Electromagnetic fields SMR = 0.84 0.691.01 Cohort Electromagnetic fields (0.250.53 lT), men RR = 0.80 0.51.3 Cohort Electromagnetic fields (0.250.53 lT), women RR = 2.0 0.84.6 Cohort Radiofrequency exposure >5 Years RR = 1.05 0.462.07 Nested casecontrol Electromagnetic fields between 4.7512.2 lT/Year RR = 1.44 0.533.91 Baker 1999 [80] Blair 2001 [74] Bertazzi 2001 [101] Fleming 1999 [148] Blair 2001 [74] Meta-analysis Casecontrol Cohort Cohort Casecontrol Teachers Health workers Dioxins (TCDD) Agriculture Agriculture >10 years exposure RR = 1.77a,e OR = 1.8 RR = 3.8a OR = 1.29 OR = 2.1a 1.222.47 0.93.6 1.212.5 0.782.02 1.04.5 a Statistically significant with p-level <0.05. b Dose-effect (or time-effect) relation. c RR related to myeloid leukaemia. d RR related to leukaemia without chronic lymphoid leukaemia. ppm = parts per million; lT = microtesla; ERR = Excess relative risk (significant when ERR do not include 0); RR = Risk ratio; SMR = Standardized mortality ratio; SIR = Standardized incidence ratio; OR = Odds ratio; CI95% = Confidence interval at 95%. e Confidence interval was at 90%. [18] also showed an association between MM mortality and combined exposure to ionizing radiation and chemicals, but the number of deaths (n = 2) from this disease was too low to justify a definitive conclusion (Table 10). The UNSCEAR report considered the available data and concluded in 2000 that no association has yet been demonstrated between ionizing radiation and MM [7]. Benzene Occupational benzene exposure has also been demonstrated to cause haematological malignancies [19]. AML. There is strong evidence that high daily exposure to benzene (more than 10 ppm) is associated with AML, and both dose-response and time-response relations have been demonstrated (Table 2) [19]. For example, 942 A. Descatha et al. Table 2. Epidemiologic surveys of occupational acute myeloid leukaemia References Wong 1995 [20] Wong 1995 [20] Wong 1995 [20] Wong 1995 [20] Hayes 1997 [21] Hayes 1997 [21] Bloemen 2004 [149] Jakobsson 1993 [22] Huebner 1997 [36] Wong 1999 [33] Sathiakumar 1995 [30] Divine 1999 [29] Brown 2002 [57] Pinkerton 2004 [126] Massoudi 1997 [55] Albin 2000 [39] Lazarov 2000 [37] Hunter 1993 [38] Kheifets 1997 [59] Theriault 1994 [67] Willett 2003 [65] Mele 1994 [72] Bethwaite 2001 [71] Cocco 1997 [78] Study design Cohort Cohort Cohort Cohort Cohort Cohort Cohort Mortality Cohort Nested casecontrol Casecontrol Cohort Cohort Cohort Casecontrol Casecontrol Casecontrol Mortality Meta-Analysis Casecontrol Casecontrol Casecontrol Casecontrol Mortality Exposure or job Benzene Benzene <200 ppm years Benzene 200400 ppm yearsc Benzene >400 ppm yearsc Benzene <10 ppm Benzene <25 ppm Benzene Gasoline (35% benzene) Petrochemical industry Gasoline (35% benzene) Petrochemical industry Petrochemical industry Male workers in the paint and varnish industry Formaldehyde Chemical industry Organic solvent (except benzene) Organic solvent Chemical laboratory Electromagnetic fields Electromagnetic fields Electromagnetic fields Child-care workers and teachers Butchers Organochlorine (DDT) Risk estimation SMR = 5.03a,b SMR = 0.91 SMR = 27.21a,b SMR = 98.37a,b RR = 3.2a,b RR = 7.1a,b SMR = 1.1 SMR = 3.60a SMR = 1.00 SMR = 1.17 OR = 2.8a SMR = 1.29 SIR = 2.2a SMR = 1.34 OR = 1.09 OR = 2.7a,b OR = 2.52a SMR = 1.92a Meta-RR = 1.40a OR = 2.25 OR = 0.91 OR = 3.3a OR = 2.6a,b PMR = 1.89 CI 95% 1.8110.97 0.025.11 3.2998.24 20.28287.65 1.010.3 2.123.7 0.302.83 1.706.60 0.561.65 0.691.85 1.17.3 0.781.99 1.04.2 0.612.54 0.402.96 1.07.3 1.454.39 1.123.08 1.161.69 0.796.46 0.691.18 1.29.0 1.16.5 0.385.52 a Statistically significant with p-level < 0.05. b Dose-effect (or time-effect) relation ppm = parts per million; Meta-RR = Meta Risk ratio; RR = Risk ratio; SMR = Standardized mortality ratio; SIR = Standardized incidence ratio; OR = Odds ratio; PMR = proportional mortality ratio; CI95% = Confidence interval at 95%. Table 3. Epidemiologic surveys of suspected occupational chronic myeloid leukaemia References Study design Exposure or job Risk estimation CI 95% Wong 2001 [28] Huebner 1997 [36] Guenel 2002 [23] Divine 1999 [29] Lewis 2000 [150] Pinkerton 2004 [126] Kheifets 1997 [59] Theriault 1994 [67] Mele 1994 [72] Cohort Cohort Cohort Cohort Cohort Cohort Meta-Analysis Casecontrol Casecontrol Petrochemical industry Petrochemical industry Benzene (high exposure group) Petrochemical industry Petrochemical industry Formaldehyde Electromagnetic fields Electromagnetic fields Child-care workers and teachers SMR = 1.31 SMR = 1.02 OR = 1.2 SMR = 1.05 SMR = 3.51a SMR = 1.39 Meta-RR = 1.24 OR = 0.61 OR = 7.8a 0.433.07 0.442.00 0.111.4 0.541.83 1.686.45 0.383.56 0.981.57 0.182.05 2.326.3 a Statistically significant with p-level < 0.05. Meta-RR = Meta Risk ratio; SMR = Standardized mortality ratio; OR = Odds ratio; CI95% = Confidence interval at 95%. two large petrochemical industry cohort studies showed Low doses of benzene and leukaemia. Although the an association between cumulative benzene exposure association between high benzene exposure and and mortality from AML [20, 21]. leukaemia is now well documented, long periods of Occupational causes of haematological malignancies Table 4. Epidemiologic surveys of suspected occupational myelodysplastic syndromes References Study design Exposure or job West 1995 [15] West 1995 [15] Rigolin 1998 [40] Rigolin 1998 [40] Casecontrol Casecontrol Casecontrol Casecontrol Ionizing radiation Halogenated organics Organic solvent Pesticides a Statistically significant with p-level < 0.05. OR = Odds ratio; CI95% = Confidence interval at 95%. Risk estimation OR = 2.05a OR = 1.57 OR = 7.11a OR = 2.12a 943 CI 95% 1.162.52 0.972.57 2.4220.88 1.263.59 Table 5. Epidemiologic surveys of suspected occupational hairy-cell leukaemia References Study design Exposure or job Clavel 1996 [106] Clavel 1996 [106] Clavel 1995 [105] Clavel 1995 [105] Nordstrom 1998 [104] Nordstrom 1998 [104] Nordstrom 1998 [104] Nordstrom 1998 [104] Casecontrol Casecontrol Casecontrol Casecontrol Casecontrol Casecontrol Casecontrol Casecontrol Pesticides Organophosphorus insecticides Agriculture employment (men) Agriculture employment (women) Fungicides Herbicides Insecticides Solvents a Statistically significant with p-level < 0.05. OR = Odds ratio; CI95% = Confidence interval at 95%. Risk estimation OR = 1.7a OR = 7.6 OR = 1.7a OR = 2.7a OR = 3.8a OR = 2.9a OR = 2.0a OR = 1.5 CI 95% 1.02.6 0.961.6 1.12.4 1.16.7 1.49.9 1.45.9 1.13.5 0.992.3 low-dose exposure have also been related to leukaemia [2225]: a cohort study of almost 75,000 workers suggests that low benzene exposure (average levels below 10 ppm) is associated with acute non-lymphocytic leukaemia (and related myelodysplastic syndromes) (Table 2) [21]. Results from a casecontrol study nested in a cohort of gas and electrical workers confirm an association between low benzene exposure and leukaemia (Table 1) [23]. However, no distinction of cell type was made, and some studies do not support this relation (Tables 1 and 2) [20, 26, 27]. Other types of leukaemia. Cohort studies of workers in the petroleum, gas and electricity industries have not shown any significant excess risk of other types of leukaemia, and in particular of chronic myeloid leukaemia (Table 3) [23, 28, 29]. Epidemiologic studies of occupational diseases, however, frequently combine acute and chronic myeloid leukaemia, and this failure to differentiate them may account in part for the absence of evidence [30]. Malignant B-cell lymphoproliferative disorders. Although limited data suggest that benzene exposure may be associated with NHL (Table 6), there is not enough evidence today to support a causal association [19, 31, 32]. Similarly, there is no evidence to support a causal association (Table 10) between occupational benzene exposure and MM [20, 26, 29, 33, 34]. Suspected occupational causes Aromatic hydrocarbons and organic solvents Myeloid leukaemia and myelodysplastic syndromes. Aromatic hydrocarbons such as xylene and toluene, which are used as substitutes for benzene, are suspected to be related to the onset of AML (Table 2). An increased risk of death from AML was observed in different cohorts of petrochemical workers exposed to benzene and other aromatic hydrocarbons [29, 30]. A casecontrol study also found an association between self-reported exposure to toluene and acute leukaemia, with a dose-response relation [35]. Nevertheless, a cohort study of 80,000 petrochemical workers exposed to hydrocarbons found no increased risk of AML [36]. Several studies report an association between exposure to organic solvents, such as aromatic hydrocarbons, and myeloid leukaemia, principally AML (Tables 2 and 3). A casecontrol study of 98 cases found a positive association between organic solvent exposure and AML [37], and a mortality study of professional chemists observed a significant excess of deaths from this cause [38]. Only one study, however, considered solvents independently of benzene exposure (Table 2) [39]. Several casecontrol studies have shown a positive association between organic solvent exposure and myelodysplastic syndromes (Table 4) [15, 40, 41], but no specific agents were identified. 944 Table 6. Epidemiologic surveys of occupational non-Hodgkin lymphoma References Study design Exposure or job Lagorio 1994 [151] Hayes 1997 [21] Wong 1999 [33] Fabbro-Peray 2001 [31] Collingwood 1996 [152] Divine 1999 [29] Huebner 2000 [52] Sathiakumar 1998 [108] Divine 2001 [107] Blair 1998 [46] Axelson 1994 [50] Hansen 2001 [51] Raaschou-Nielsen 2003 [49] Boice 1999 [56] Anttila 1995 [47] Rafnsson 2001 [153] Hansen 1994 [132] Massoudi 1997 [55] Hardell 1994 [91] Blair 1993 [42] Mao 2000 [154] Mao 2000 [154] Rego 2002 [45] Rego 2002 [45] Tatham 1997 [44] Demers 1998 [155] Sont 2001 [16] Schroeder 1997 [68] Morgan 2000 [64] Cano 2001 [66] Villeneuve 2000 [60] Theriault 1994 [67] Fabbro-Peray 2001 [31] Baker 1999 [80] Blair 1992 [73] Khuder 1998 [83] Baris 1998 [89] Gambini 1997 [96] Burns 2001 [156] Kelleher 1998 [77] Thorn 2000 [92] Zahm 1997 [93] Zahm 1997 [93] Cano 2001 [66] MacLennan 2003 [157] Rusiecki 2004 [100] Acquavella 2004 [98] Bertazzi 2001 [101] Metayer 1998 [88] Amadori 1995 [79] Hardell 1994 [91] Hardell 1994 [91] Fabbro-Peray 2001 [31] Mao 2000 [154] De Roos 2003 [95] Cohort Cohort Nested casecontrol Casecontrol Cohort Cohort Cohort Cohort Cohort Cohort Cohort Cohort Cohort Cohort Cohort Cohort Cohort Casecontrol Casecontrol Casecontrol Casecontrol Casecontrol Casecontrol Casecontrol Casecontrol Meta-Analysis Cohort Cohort Cohort Cohort Nested casecontrol Casecontrol Casecontrol Meta-Analysis Meta-Analysis Meta-Analysis Meta-Analysis Cohort Cohort Cohort Cohort Cohort Cohort Cohort Cohort Cohort Cohort Cohort Nested casecontrol Casecontrol Casecontrol Casecontrol Casecontrol Casecontrol Casecontrol Benzene (35%) Benzene >10 years Benzene (35%) Benzene >810 days Petrochemical industry Petrochemical industry Petrochemical industry Butadiene and styrene Butadiene Trichloroethylene Trichloroethylene Trichloroethylene Trichloroethylene (high exposure) Trichloroethylene Halogenated hydrocarbons Typesetters Pharmacy dispenser (long term) Chemical industry Solvents Typesetters >10 years Benzidine Lubricating oils Organic solvents Organic solvents + domestic pesticides Solvents Wood-workers Ionizing radiation Electromagnetic fields >20 years Radiofrequency exposure >5 years Communication and transport (except pilots and postmen) (Electromagnetic field) Electromagnetic fields >40 V/m Electromagnetic fields Radio operator Teachers Agriculture Agriculture DDT exposure (pesticides) Rice growers >20 years of exposure 2.4-D (herbicide) Farmers Herbicides (phenoxyacetic acids) Pesticides Pesticides >3 years Agriculture Triazine herbicides Triazine herbicides Alachlor herbicides, high exposure Dioxins (TCDD) Abattoir workers (viruses) Breeders (agriculture) Herbicides (phenoxyacetic acids) Chlorophenols Agriculture Herbicides and pesticides Triazine and Alachlor herbicides A. Descatha et al. Risk estimation SMR = 1.58 RR = 4.2a SMR = 0.42 OR = 4.6a SMR = 1.32 SMR = 0.88 SIR = 1.06 SMR = 0.91 SMR = 1.48 RR = 2 SIR = 1.56 SIR = 3.5a SIR = 1.5a SMR = 1.19 SIR = 2.13a SIR = 4.46a SIR = 3.7a OR = 3.11a OR = 2.4a OR = 2.5a,b OR = 1.9a OR = 1.3a OR = 1.67 OR = 2.24a OR = 1.60a,c SMR = 1.08 Risk excess (by Sv) = 6.6 RR = 1.40 RR = 0.64 RR = 2.43 to 3.43a CI 95% 0.434.08 1.115.9 0.250.65 1.119.2 0.742.17 0.691.11 0.671.61 0.611.32 0.892.31 0.94.6 0.513.64 1.56.9 1.22.0 0.651.99 1.063.80 1.639.70 1.28.9 1.108.82 1.43.9 1.15.7 1.13.4 1.01.5 0.972.87 1.013.97 1.102.20 0.811.39 0.028.3d 0.802.30 0.321.15 p < 0.05 OR = 3.57a,b OR = 1.22 OR = 3.1a RR = 1.36a Meta-RR = 1.05 Meta-OR = 1.10a OR = 1.2a SMR = 3.38 SMR = 1.00 SIR = 1.69a SIR = 1.92b SMR = 1.14b SMR = 7.11a RR = 0.96 SMR = 3.72a RR = 1.61 SIR = 2.07 RR = 2.8a OR = 12a OR = 2.22a OR = 5.5a OR = 4.8a OR = 1.5a OR = 1.3a OR = 2.1a 1.309.80 0.771.94 1.46.6 1.131.62 0.981.12 1.031.19 1.01.6 0.928.65 0.212.92 1.242.66 0.0310.7 0.312.91 1.7828.42 0.881.04 1.019.52 0.624.16 0.436.04 1.17.0 1.1130.6 1.164.26 2.711 2.78.8 1.02.1 1.01.6 1.13.9 Occupational causes of haematological malignancies 945 Table 6. (Continued) References Study design Exposure or job Risk estimation CI 95% De Roos 2003 [95] Kato 2004 [97] Zheng 2001 [90] Garabedian 1999 [158] Fritschi 2002 [82] Lee 2002 [76] Cerhan 1998 [85] Casecontrol Casecontrol Casecontrol Casecontrol Casecontrol Mortality Mortality Triazine herbicides and Diazinon insecticides Pesticides 1018 years (women) Carbamate (herbicides and insecticides) Chlorophenol >8 years Workers with animals Breeders Agriculture OR = 3.9a OR = 2.72a OR = 1.5a OR = 1.51 OR = 1.8a PMR = 1.17a PMR = 1.09 1.78.8 1.375.40 1.12.0 0.882.59 1.12.9 1.061.30 0.961.23 a Statistically significant with p-level < 0.05. b Dose-effect (or time-effect) relation. c OR related to small cell diffuse lymphoma. d Confidence interval at 90%. lT = microtesla; Meta-RR = Meta risk ratio; Meta-OR = Meta odds ratio; RR = Risk ratio; SMR = Standardized mortality ratio; SIR = Standardized incidence ratio; OR = Odds ratio; PMR = proportional mortality ratio; CI95% = Confidence interval at 95%. Table 7. Epidemiologic surveys of suspected occupational Hodgkin disease References Study design Exposure or job Risk estimation CI 95% Wong 2001 [28] Wong 1999 [33] Sathiakumar 1998 [108] Blair 1998 [46] Axelson 1994 [50] Hunter 1993 [38] Sont 2001 [16] Morgan 2000 [64] Schroeder 1997 [68] Theriault 1994 [67] Khuder 1999 [84] Blair 1992 [73] Pukkala 1997 [159] Swaen 1992 [102] Bertazzi 2001 [101] Metayer 1998 [88] Pahwa 2003 [160] Cerhan 1998 [85] Khuder 1998 [83] Blair 1992 [73] Pukkala 1997 [159] Swaen 1992 [102] Bertazzi 2001 [101] Metayer 1998 [88] Pahwa 2003 [160] Cerhan 1998 [85] Cohort Nested casecontrol Cohort Cohort Cohort Mortality Cohort Cohort Cohort Casecontrol Meta-Analysis Meta-Analysis Cohort Cohort Cohort Nested casecontrol Casecontrol Mortality Meta-Analysis Meta-Analysis Cohort Cohort Cohort Nested casecontrol Casecontrol Mortality Petrochemical industry Benzene (35%) Butadiene and styrene Trichloroethylene Trichloroethylene Chemistry Ionizing radiation Radiofrequency exposure >5 years Electromagnetic fields >20 years Electromagnetic fields Agriculture Agriculture Farmers (without animals) Pesticides Dioxins (TCDD) Abattoir workers (viruses) Farmers Agriculture Agriculture Agriculture Farmers (without animals) Pesticides Dioxins (TCDD) Abattoir workers (viruses) Farmers Agriculture SMR = 0.61 SMR = 0.48 SMR = 0.95 RR = 1.4 SIR = 1.07 SMR = 0.51a Risk excess (by Sv) = 64.8 RR = 1.14 RR = 1.1 OR = 1.33 RR = 1.25a Meta-RR = 1.16a SIR = 1.74a SMR = 3.34 RR = 4.9a OR = 12a OR = 0.95 PMR = 1.62a RR = 1.25a Meta-RR = 1.16a SIR = 1.74a SMR = 3.34 RR = 4.9a OR = 12a OR = 0.95 PMR = 1.62a 0.131.77 0.181.05 0.411.87 0.212 0.035.95 0.2180.996 0.0591.3b 0.313.10 0.34.4 0.652.70 1.111.42 1.031.29 1.122.59 0.0418.61 1.516.4 1.1130.6 0.611.48 1.042.54 1.111.42 1.031.29 1.122.59 0.0418.61 1.516.4 1.1130.6 0.611.48 1.042.54 a Statistically significant with p-level < 0.05. b Confidence interval at 90%. Meta-RR = Meta risk ratio; Meta-OR = Meta odds ratio; RR = Risk ratio; SMR = Standardized mortality ratio; SIR = Standardized incidence ratio; OR = Odds ratio; PMR = proportional mortality ratio; CI95% = Confidence interval at 95%. Malignant B-cell lymphoproliferative disorders. An association is also suspected between organic solvent exposure and NHL [4244]. One study in particular [45] suggests that occupational organic solvent exposure is associated with an excess risk of NHL, especially among workers using household insecticides. Several cohort studies found an association between exposure to trichloroethylene (Table 6), a solvent used especially in the aviation sector, and NHL [4651]. 946 A. Descatha et al. Table 8. Epidemiologic surveys of suspected occupational acute lymphoid leukaemia References Study design Exposure or job Risk estimation CI 95% Divine 1999 [29] Kheifets 1997 [59] Theriault 1994 [67] Blair 2001 [74] Willett 2003 [65] Kelleher 1998 [77] Bethwaite 2001 [71] Mele 1994 [72] Cohort Meta-Analysis Casecontrol Casecontrol Casecontrol Cohort Casecontrol Casecontrol Petrochemical industry Electromagnetic fields Electromagnetic fields Electromagnetic fields Electromagnetic fields Agriculture Butchers Agriculture SMR = 1.01 Meta-RR = 1.33 OR = 2.07 OR = 2.4 OR = 1.70 SIR = 1.87a OR = 4.0a OR = 1.0 0.322.35 0.931.92 0.1235.25 0.78.8 0.863.35 1.132.92 1.016.1 0.42.5 a Statistically significant with p-level < 0.05. b Dose-effect (or time-effect) relation. c Confidence interval was at 90% in this study. Meta-RR = Meta risk ratio; Meta-OR = Meta odds ratio; RR = Risk ratio; SMR = Standardized mortality ratio; SIR = Standardized incidence ratio; OR = Odds ratio; PMR = proportional mortality ratio; CI95% = Confidence interval at 95%. Table 9. Epidemiologic surveys of suspected occupational chronic lymphoid leukaemia References Study design Exposure or job Risk estimation CI 95% Huebner 1997 [36] Huebner 2000 [52] Lewis 2000 [150] Divine 1999 [29] Hunter 1993 [38] Kheifets 1997 [59] Theriault 1994 [67] Kelleher 1998 [77] Amadori 1995 [79] Lee 2002 [76] Cohort Cohort Cohort Cohort Mortality Meta-Analysis Casecontrol Cohort Casecontrol Mortality Petrochemical industry Petrochemical industry Petrochemical industry Petrochemical industry Chemical laboratory Electromagnetic Fields Electromagnetic Fields Agriculture Farmers-breeders Farmers-breeders SMR = 1.60 SIR = 1.22 SMR = 3.51a SMR = 0.8 SMR = 1.79a Meta-RR = 1.55a OR = 1.40 SIR = 1.88a OR = 3.05a PMR = 1.28a 0.852.73 0.402.85 1.686.45 0.451.33 1.002.95 1.102.19 0.523.77 1.342.56 1.128.32 1.061.53 a Statistically significant with p-level < 0.05. Meta-RR = Meta risk ratio; SMR = Standardized mortality ratio; SIR = Standardized incidence ratio; OR = Odds ratio; PMR = proportional mortality ratio; CI95% = Confidence interval at 95%. Exposure to other aromatic hydrocarbons in petrochemical plants [29, 52] or in occupations such as painting, printing or aircraft manufacture [5357] has been suspected of inducing MM, but a meta-analysis of 22 cohorts did not support this association (Table 10) [58]. Electromagnetic fields Leukaemia. A meta-analysis suggests that occupational exposure to electromagnetic fields, including low frequency and extremely low frequency fields, may be associated with AML (small but significant increase in risk) and CLL in electrical industry workers [59]. A casecontrol study nested in a cohort of electric utility workers explored the relation between a series of indices of electric and magnetic field exposure and the incidence of leukaemia; its aim was to identify the most appropriate exposure indicator for risk assessment. A significant association was found between exposure to electric fields above 10 V/m and leukaemia [60], but these results have not been confirmed by recent studies in the industry (Tables 1 and 2) [6165]. Malignant B-cell lymphoproliferative disorders. Some data from the electricity and telecommunications industries suggest a relation between electromagnetic field exposure and NHL or MM (Tables 6 and 10) [6669]. A slight positive association between electromagnetic field exposure for a duration up to 20 years and low-grade NHL was found in a cohort of electric utility workers [68]. No association was observed between electromagnetic fields and MM in this study. A cohort study of workers in the engineering industry did, however, suggest an association between high levels of extremely low frequency magnetic fields and MM [63]. Occupational causes of haematological malignancies 947 Table 10. Epidemiologic surveys of suspected occupational multiple myeloma References Study design Exposure or job Risk estimation CI 95% Sonoda 2001 [130] Sonoda 2001 [130] Sonoda 2001 [130] Lee 2003 [129] Wong 1995 [20] Rinsky 2002 [26] Wong 1999 [33] Wong 1997 [58] Divine 1999 [29] Huebner 2000 [52] Meta-Analysis Meta-Analysis Meta-Analysis Cohort Cohort Cohort Nested casecontrol Meta-Analysis Cohort Cohort Benzene/solvents Petroleum Engine exhaust Engine exhaust (diesel) Benzene Benzene Benzene 35% Petrochemical industry Petrochemical industry Petrochemical industry Meta-OR = 0.74a Meta-OR = 1.11 Meta-OR = 1.34a RR = 1.3a SMR = 2.91 SMR = 2.04 SMR = 0.79 SMR = 0.93 SMR = 1.01 SIR = 1.39 0.60.9 0.961.28 1.141.57 1.001.77 0.797.45 0.664.76 0.461.24 0.811.07 0.71.4 0.642.64 Blair 1998 [46] Axelson 1994 [50] Anttila 1995 [47] Lundberg 1998 [161] Sathiakumar 1998 [108] Cohort Cohort Cohort Cohort Cohort Trichloroethylene Trichloroethylene Trichloromethane or tetrachloroethane Organic solvents >5 years Butadiene and styrene RR = 1.3 SIR = 0.57 SIR = 15.98a SIR = 3.8 SMR = 0.92 0.53.4 0.013.17 1.9357.7 0.811 0.51.55 Brown 2002 [57] Demers 1993 [54] Massoudi 1997 [55] Baysson 2000 [18] Schroeder 1997 [68] Hakansson 2002 [63] Hakansson 2002 [63] Cohort Casecontrol Casecontrol Cohort Cohort Cohort Cohort Male painters Painters >10 years Chemical industry SIR = 1.0 OR = 4.1a, b OR = 2.39a Ionizing radiation and chemicals Electromagnetic fields >20 years Electromagnetic fields 0.1640.25 lT (medium exposure) Electromagnetic fields 0.250.53 lT (high exposure) SMR = 8.38a RR = 0.9 RR = 2.9b RR = 3.8 0.81.2 1.810.4 1.045.48 1.4426.2 0.41.8 0.810.7 0.915.6 Theriault 1994 [67] Baker 1999 [80] Robinson 1999 [162] Blair 1992 [73] Pukkala 1997 [159] Swaen 1992 [102] Baris 2004 [163] Lee 2004 [99] Metayer 1998 [88] Nanni 1998 [103] Demers 1993 [54] Cocco 1997 [78] Cerhan 1998 [85] Lee 2002 [76] Casecontrol Meta-Analysis Mortality Meta-Analysis Cohort Cohort Cohort Cohort Nested casecontrol Casecontrol Casecontrol Mortality Mortality Mortality Electromagnetic fields Teachers Teachers Agriculture Agriculture (men only) Pesticides Pesticides Alachlor herbicides Supermarket meat-cutters Organochlorine Pesticides (high exposure) DDT (pesticides) Agriculture Breeders OR = 1.06 Meta-PMR = 1.58a PMR = 1.23a Meta-RR = 1.12a SIR = 0.95 SMR = 8.15a OR = 1.3 RR = 5.66 OR = 18a OR = 2.4a OR = 5.2a, b SMR = 3.41a PMR = 1.17 PMR = 1.19a 0.442.53 1.471.70 1.061.43 1.041.21 0.821.10 1.6423.82 0.91.8 0.7045.7 1.6207.95 1.05.9 1.9621.1 1.107.95 0.981.40 1.031.38 a Statistically significant with p-level < 0.05. b Dose-effect (or time-effect) relation. lT = microtesla Meta-RR = Meta risk ratio; Meta-OR = Meta odds ratio; Meta-PMR = Meta proportional mortality ratio; RR = Risk ratio; SMR = Standardized mortality ratio; SIR = Standardized incidence ratio; OR = Odds ratio; PMR = proportional mortality ratio; CI95% = Confidence interval at 95%. Based in part on studies of haematopoietic cancer, IARC considers electromagnetic fields to be a possible carcinogenic hazard (group 2B). Further studies are needed [70]. Infectious agents Myeloid malignancies. Some casecontrol studies suggest that myeloid diseases, especially AML, may be related to exposure to infectious agents among occupational groups as diverse as butchers [71] and teachers [72]. These studies did not, however, take into account confounding factors, such as exposure to chemicals in the meat industry [71]. Malignant B-cell lymphoproliferative disorders. Among agricultural workers, occupational exposure to infectious agents [7378] is suspected of increasing the risk of lymphoproliferative malignancies (Tables 69). A casecontrol study among meat industry workers showed a significant association and a time-effect 948 A. Descatha et al. relation between exposure to infectious agents in abattoirs and leukaemia (especially acute lymphoid leukaemia) [71]. A population-based casecontrol study found a significant association between work as a farmer-breeder and CLL [79]. Although some animal retroviruses, such as bovine leukaemia virus (BLV) and bovine immunodeficiency virus, are suspected, no specific infectious agents have been identified. Some studies support a causal association between occupational exposure to viruses and NHL, especially among teachers [80] and breeders (Table 6) [31, 76, 81]. Two casecontrol studies found a positive association between working with animals and NHL [79, 82]. These results are consistent with the results of a meta-analysis of NHL risk among farmers [83]. Several viruses are suspected: Epstein Barr (EBV) and human T-cell leukaemia for human transmission and BLV for animal contacts [82, 83]. Exposure to infectious agents is also thought to increase the risk of Hodgkin disease [73, 84, 85] (Table 7), mainly in the teaching and medical sectors, where its incidence is higher than in the general population [86, 87]. Nevertheless, no specific agent except EBV has been clearly related to occupational Hodgkin disease [84]. Infectious agents, especially viruses, are also suspected of causing MM mortality: two studies found elevated mortality from MM among teachers (Table 10) [80]. A nested casecontrol study in a cohort of meat industry workers also showed an increased risk of MM among male supermarket cutters [88]. Pesticides Malignant B-cell lymphoproliferative disorders. Several studies report a consistent, significant, and positive association (Table 6) between occupational pesticide exposure and NHL [89100]. The classes of pesticides involved have not been clearly identified. A pooled data meta-analysis examined organochlorine exposure but found no strong consistent evidence for its association with NHL [89]. A population-based casecontrol study suggests an increased risk of NHL associated with carbamate pesticides (insecticides and herbicides) [90]. Several different casecontrol and cohort studies [9193] suggest that phenoxyacetic acid exposure may be linked to NHL (Table 6). Others, however, suggest that these results are due to the contamination of phenoxyacetic acid herbicides by dioxins (TCDD) [83], which are also possible haematopoietic carcinogens, as indicated by data from the Seveso cohort [101]. A multicenter casecontrol study found several other pesticides, including insecticide oils and triazine, to be significantly associated with NHL (combined with CLL) [94]. Excess risks of CLL (Table 9) and of MM (Table 10) have been found in various studies among farmers [54, 73, 102], and pesticide exposure has been suggested as the cause. Except for chlorinated pesticides [78, 103], no specific agents were identified [76, 77, 79]. Three casecontrol studies also point to an association between occupational pesticide exposure and hairy cell leukaemia (Table 5) [104106]. Myeloid malignancies. An excess risk of myelodysplastic syndromes was only associated with pesticide exposure in a casecontrol study (Table 4) [40]. Other chemical agents 1,3-butadiene. 1,3-butadiene, mostly used in the rubber and plastic industries, is considered a probable carcinogen by IARC (group 2A). Several studies show it to be positively associated with haematological malignancies, especially leukaemia [107111]. However, a study of the haematological data of employees from a petrochemical facility possibly exposed to 1,3-butadiene monomer found a mortality rate from all lymphohaematopoietic cancers approximately the same as in the reference population (SMR, 1.06; 95% CI, 0.223.11) [112]. Styrene. Styrene, also used in the plastic industry, is considered a possible carcinogenic agent by IARC (group 2B), and its metabolite styrene oxide a probable carcinogen (group 2A). A historical cohort study left open a possible excess risk of leukaemia in styrene-exposed workers [113], but no excess risk of mortality from leukaemia was observed in a cohort study of 5204 such workers [114]. Ethylene oxide. Ethylene oxide is used as a sterilizing agent or intermediary in chemical synthesis and has been classified by IARC as certainly carcinogenic to the haematopoietic system (group 1) [115117]. An extended mortality follow-up of a cohort of 18,235 men and women exposed to ethylene oxide found no overall excess of haematopoietic cancer or any specific type of haematopoietic cancer (Table 1), but a significant trend was seen in the exposure-response (haematopoietic cancer) relation among men [118]. An other extended mortality follow up of workers exposed to ethylene oxide also concluded that balance of evidence from epidemiologic data indicates that haematopoietic cancer from ethylene expose are low [117]. Occupational causes of haematological malignancies 949 Alkylating antineoplastic drugs. In recent decades, conclusive evidence has demonstrated that high dose of alkylating antineoplastic drugs can cause AML in patients with cancer. These drugs are thus suspectedof increasing the risk of leukaemia among healthcare workers [119, 120], and occupational studies have indeed found an excess risk of leukaemia in this occupational category [119, 121123]. These data are based on relatively few cases, however, and need to be confirmed by larger studies. Formaldehyde. Exposure to formaldehyde has reportedly been associated with leukaemia, especially in three broad occupational groups: embalmers, anatomists, and formaldehyde industrial workers [124]. Two large cohort studies on industrial workers have recently found a significant association between formaldehyde exposure and increased leukaemia rates [125, 126]. However, a recent large cohort study with higher exposure to formaldehyde and a larger number of workers than the two others failed to confirm this conclusion [127]. The lack of consistency of the data across epidemiology studies [127, 128] and the absence of biological plausibility lead us to conclude that there is no demonstrated evidence of a causal relation between formaldehyde exposure and leukaemia [124]. Miscellaneous. Causal relations have been also proposed but not demonstrated between exposure to engine exhaust and MM [129, 130], wood exposure and Hodgkin disease [86], hair dye exposure and lymphoproliferative cancers [131], and biomedical laboratory products and haematological malignancies [132137]. Discussion and conclusion Causal relations are now well-documented between haematopoietic cancers, especially AML, and high levels of exposure to benzene and to ionizing radiation. Infectious agents and pesticides are strongly suspected of inducing lymphoproliferative cancers. Some studies also show associations between haematological malignancies and exposure to low levels of benzene, ionizing radiation, organic solvents, cytostatic drugs, and ethylene oxide. Despite the many studies of occupational risk factors, haematological malignancies due to occupational exposure have not been adequately studied in epidemiologic situations. Their relative rarity, histological diversity, long latency periods, and confounding factors, including genetic factors, all help explain this lack of study. Moreover, precise exposure assessment, both qualitative and quantitative, is too often absent. Specifically, too little information is collected about the types of pesticides, solvents and infectious agents [138140]. Nevertheless, epidemiologic studies have provided hypotheses about several occupational hazards. Their role in the development of haematological malignancies must be documented by other research, including molecular analysis and toxicological experiments to explain mechanisms and pathways [39, 141]. Similarly, at the individual level, clinicians find the occupational associations of their patients' diseases obscured by long latency periods, insufficient information about occupational history, and other factors. Aid from specialists in occupational health and in toxicology is essential to enable clinicians to make the difficult linkage between occupation and disease. Improved recognition of the occupational source of haematological malignancies is needed. Workers' compensation is available when these diseases are considered to be related to benzene or ionizing radiation, for instance, in France [5], Germany [142], and Italy [143]. Better identification of these occupational haematological malignancies by clinicians might also improve their prevention. Acknowledgements We would like to thank Janet Gadal, Jo Ann Cahn and Dr Bradley Evanoff who gently corrected our English. References 1. Nisse C, Fenaux P (2000) He mopathies malignes In: Pairon JC, Brochard P, Le Bourgeois JP, Ruffie P, Les Cancers Professionnels. pp. 497535. Paris: Margaux Orange. 2. Hardell L, Eriksson M (2003) Is the decline of the increasing incidence of non-Hodgkin lymphoma in Sweden and other countries a result of cancer preventive measures? Environ Health Perspect 111: 17041706. 3. Doll R, Peto R (1981) The causes of cancer: quantitative estimates of avoidable risks of cancer in the United States today. J Natl Cancer Inst 66: 11911308. 4. 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