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

Abstract

BackgroundPrevious 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.ObjectivesWe used natural splines in a flexible meta-regression method to assess the shape of the benzene–leukemia ERC.MethodsWe 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.ResultsThe 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.ConclusionsAlthough 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.

Occupational exposure to solvents and acute myeloid leukemia: a population-based, case–control study in four Nordic countries

“…In an Italian multicenter case-control study no association between exposure to solvents and AML was found (16). Excess risk of AML from benzene exposure could be identifiable already at 10 ppm/year exposure levels according to Vlaanderen et al (8). The estimated cumulative benzene exposure in our study exceeded 13.6 ppm/year for 68 cases and 418 controls (table 3).…”

Avaliação ambiental de BTEX (benzeno, tolueno, etilbenzeno, xilenos) e biomarcadores de genotoxicidade em trabalhadores de postos de combustíveis

“…Rappaport et al 39 , por meio da comparação de modelos cinéticos de duas vias metabólicas do benzeno, sugerem maior risco de leucemia em baixos níveis ambientais de exposição. Confirmando essa suposição, Vlaanderen et al 40 realizaram um estudo de metanálise por metarregressão com o objetivo de avaliar a curva dose--resposta benzeno e risco de leucemia, sendo indicado pelo modelo uma forma supralinear da curva dose-resposta na região de baixas doses de exposição ao benzeno. Provavelmente, esse resultado de maior risco de leucemia em baixas doses ocorre pelo benzeno ser mais eficientemente metabolizado em baixas concentrações, aumentando a produção de seus metabólitos reativos, que são hematotóxicos [41][42][43][44] .…”

Attenuation of Exposure-response Rate Ratios at Higher Exposures

“…More recent occupational examples can be found for lung cancer and diesel fumes, breast cancer and ethylene oxide, and leukemia and benzene. [6][7][8] nonoccupational examples can be found in cohort studies assessed by Pope et al, 9 and Smith and Peel, 10 where rrs for heart disease attenuate over time with increasing exposure to fine particles (PM 2.5 ) from air pollution or cigarettes.…”