title: Flexible meta-regression to assess the shape of the benzene-leukemia exposure-response curve.
abstract: BACKGROUND
  Previous evaluations of the shape of the benzene-leukemia exposure-response curve (ERC) were based on a single set or on small sets of human occupational studies. Integrating evidence from all available studies that are of sufficient quality combined with flexible meta-regression models is likely to provide better insight into the functional relation between benzene exposure and risk of leukemia.
  
  
  OBJECTIVE
  We used natural splines in a flexible meta-regression method to assess the shape of the benzene-leukemia ERC.
  
  
  METHODS
  We fitted meta-regression models to 30 aggregated risk estimates extracted from nine human observational studies and performed sensitivity analyses to assess the impact of a priori assessed study characteristics on the predicted ERC.
  
  
  RESULTS
  The natural spline showed a supralinear shape at cumulative exposures less than 100 ppm-years, although this model fitted the data only marginally better than a linear model (p = 0.06). Stratification based on study design and jackknifing indicated that the cohort studies had a considerable impact on the shape of the ERC at high exposure levels (> 100 ppm-years) but that predicted risks for the low exposure range (< 50 ppm-years) were robust.
  
  
  CONCLUSIONS
  Although limited by the small number of studies and the large heterogeneity between studies, the inclusion of all studies of sufficient quality combined with a flexible meta-regression method provides the most comprehensive evaluation of the benzene-leukemia ERC to date. The natural spline based on all data indicates a significantly increased risk of leukemia [relative risk (RR) = 1.14; 95% confidence interval (CI), 1.04-1.26] at an exposure level as low as 10 ppm-years.
authors.affiliation: Institute for Risk Assessment Sciences, Utrecht University, Utrecht, the Netherlands. J.J.Vlaanderen@uu.nl
authors.forename: Jelle
authors.initials: J
authors.lastname: Vlaanderen
authors.forename: Lützen
authors.initials: L
authors.lastname: Portengen
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Rothman
authors.forename: Qing
authors.initials: Q
authors.lastname: Lan
authors.forename: Hans
authors.initials: H
authors.lastname: Kromhout
authors.forename: Roel
authors.initials: R
authors.lastname: Vermeulen
mesh_terms: D001554:Benzene / Q000633:toxicity*; D006801:Humans; D007938:Leukemia / Q000139:chemically induced / Q000453:epidemiology*; D016273:Occupational Exposure; D012044:Regression Analysis
chemical_list: D001554:Benzene