Flexible Meta-Regression to Assess the Shape of the Benzene–Leukemia Exposure–Response Curve

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. OBJECTIVES: 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.