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Occupational Exposure Assessment, Metabolism, and Health Effects of Benzene Exposure
thesisposted on 01.12.2020, 00:00 by Madhawa Saranadasa
Benzene is a ubiquitous hydrocarbon that has several natural and anthropogenic sources. When absorbed in the body, benzene is metabolized into toxic intermediates that accumulate in the bone marrow and generate reactive oxygen species. This eventually leads to damage to hematopoietic progenitor cells and culminates in perturbations of hematologic parameters and several types of blood tissue malignancies. This work aimed to examine several aspects of benzene toxicity including occupational exposure, kinetics of metabolism and environmental exposure. Aim 1 of this work established an exposure reconstruction methodology for the Four Refinery Cohort that generated estimate of cumulative exposure. These exposure estimates can be used in future epidemiological investigations to evaluate the health effects of occupational exposure to benzene in a modern context. Aim 2 of this work modelled the dose-response relationship between occupational benzene exposure and the production of metabolites using data from the Shanghai Health Study. The modeled relationships exhibited a clear dose-response with non-linearities that are consistent with enzyme kinetics. The models were further extended to assess whether functional polymorphisms in genes related to benzene metabolism modified the dose-response relationship. These findings further elucidate the kinetics of benzene toxicity which can help to inform benzene regulatory standards and protect workers. Aim 3 of this work evaluated the association between environmental exposure to a mixture of volatile organic chemicals (benzene, toluene, ethylbenzene, xylene, and styrene) and hematologic parameters among a subset of participants in the National Health and Nutrition Examination Survey. We specifically focused on implementing mixture methods to understand the overall health effects of the mixture and to further identify the individual components that are driving these effects. Two mixture methods were used: Bayesian kernel machine regression and quantile g-computation. In sum, this work investigated occupational exposure assessment, molecular mechanisms of benzene toxicity and hematologic manifestations of toxicity to provide an integrated understanding of the health effects of human exposure to benzene. These results can help to inform occupational exposure limits and environmental risk characterization.