title: A case-control study to investigate the risk of leukaemia associated with exposure to benzene in petroleum marketing and distribution workers in the United Kingdom.
abstract: OBJECTIVE
  To investigate the risk of leukaemia in workers in the petroleum distribution industry who were exposed to low levels of benzene.
  
  
  METHODS
  From the cohort of distribution workers, 91 cases were identified as having leukaemia on either a death certificate or on cancer registration. These cases were compared with controls (four per case) randomly selected from the cohort, who were from the same company as the respective case, matched for age, and alive and under follow up at the time of case occurrence. Work histories were collected for the cases and controls, together with information about the terminals at which they had worked, fuel compositions, and occupational hygiene measurements of benzene. These data were used to derive quantitative estimates of personal exposure to benzene. Odds ratios (OR) were calculated conditional on the matching, to identify those variables in the study which were associated with risk of leukaemia. Examination of the potential effects of confounding and other variables was carried out with conditional logistic regression. Analyses were carried out for all leukaemia and separately for acute lymphoblastic, chronic lymphocytic, acute myeloid and monocytic, and chronic myeloid leukaemias.
  
  
  RESULTS
  There was no significant increase in the overall risk of all leukaemias with higher cumulative exposure to benzene or with intensity of exposure, but risk was consistently doubled in subjects employed in the industry for > 10 years. Acute lymphoblastic leukaemia tended to occur in workers employed after 1950, who started work after the age of 30, worked for a short duration, and experienced low cumulative exposure with few peaks. The ORs did not increase with increasing cumulative exposure. The risk of chronic lymphocytic leukaemia seemed to be related most closely to duration of employment and the highest risk occurred in white collar workers with long service. These workers had only background levels of benzene exposure. There was no evidence of an association of risk with any exposure variables, and no evidence of an increasing risk with increasing cumulative exposure, mean intensity, or maximum intensity of exposure. The patterns of risk for acute myeloid and monocytic leukaemia were different from those of the lymphoid subgroups, in which duration of employment was the variable most closely related to risk. Risk was increased to an OR of 2.8 (95% confidence interval (95% CI) 0.8 to 9.4) for a cumulative exposure between 4.5 and 45 ppm-years compared with < 0.45 ppm-years. For mean intensity between 0.2 and 0.4 ppm an OR of 2.8 (95% CI 0.9 to 8.5) was found compared with < 0.02 ppm. Risk did not increase with cumulative exposure, maximum intensity, or mean intensity of exposure when treated as continuous variables. Cases of acute myeloid and monocytic leukaemia were more often classified as having peaked exposures than controls, and when variables characterising peaks, particularly daily and weekly peaks, were included in the analysis these tended to dominate the other exposure variables. However, because of the small numbers it is not possible to distinguish the relative influence of peaked and unpeaked exposures on risk of acute myeloid and monocytic leukaemia. There was no evidence of an increased risk of chronic myeloid leukaemia with increases in cumulative exposure, maximum intensity, mean intensity, and duration of employment, either as continuous or categorical variables. Analyses exploring the sensitivity of the results to the source and quality of the work histories showed similar patterns in general. However, no increases in ORs for categories of cumulative exposure were found for acute myeloid and monocytic leukaemia in the data set which included work histories obtained from personnel records still in existence, although numbers were reduced. Analyses excluding the last five and 10 years of exposure showed a tendency for ORs to reduce for chronic lymphocytic leukaemia and chronic myeloid leukaemia, and to increase for acute myeloid and monocytic leukaemia. Limitations of the study include uncertainties and gaps in the information collected, and small numbers in subcategories of exposure which can lead to wide CIs around the risk estimates and poor fit of the mathematical models.
  
  
  CONCLUSIONS
  There is no evidence in this study of an association between exposure to benzene and lymphoid leukaemia, either acute or chronic. There is some suggestion of a relation between exposure to benzene and myeloid leukaemia, in particular for acute myeloid and monocytic leukaemia. Peaked exposures seemed to be experienced for this disease. However, in view of the limitations of the study, doubt remains as to whether the risk of acute myeloid and monocytic leukaemia is increased by cumulative exposures of < 45 ppm-years. Further work is recommended to review the work histories and redefine their quality, to explore the discrepancies between results for categorical and continuous variables, and to develop ranges around the expose estimates to enable further sensitivity analyses to be carried out.
authors.affiliation: Department of Public Health Medicine and Epidemiology, University of Nottingham, Queen's Medical Centre.
authors.forename: L
authors.initials: L
authors.lastname: Rushton
authors.forename: H
authors.initials: H
authors.lastname: Romaniuk
mesh_terms: D001554:Benzene / Q000009:adverse effects*; D016022:Case-Control Studies; D015331:Cohort Studies; D003644:Death Certificates; D006801:Humans; D007938:Leukemia / Q000139:chemically induced / Q000453:epidemiology*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000139:chemically induced / Q000453:epidemiology; D007948:Leukemia, Monocytic, Acute / Q000139:chemically induced / Q000453:epidemiology; D007951:Leukemia, Myeloid / Q000139:chemically induced / Q000453:epidemiology; D016015:Logistic Models; D008297:Male; D009784:Occupational Diseases / Q000139:chemically induced / Q000453:epidemiology*; D016273:Occupational Exposure / Q000009:adverse effects* / Q000032:analysis; D016017:Odds Ratio; D010578:Petroleum; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000139:chemically induced / Q000453:epidemiology; D012042:Registries; D014186:Transportation; D006113:United Kingdom / Q000453:epidemiology
chemical_list: D010578:Petroleum; D001554:Benzene