Pulmonary Metabolism of BenzeneEPA Grant Number: R826191
Title: Pulmonary Metabolism of Benzene
Investigators: Carlson, Gary P.
Institution: Purdue University
EPA Project Officer: Saint, Chris
Project Period: October 20, 1997 through October 19, 2000
Project Amount: $389,120
RFA: Exploratory Research - Human Health (1997) RFA Text | Recipients Lists
Research Category: Health Effects , Human Health , Health
Human exposure to benzene is widespread and occurs primarily via inhalation. Benzene is associated with leukemia due to the action of its metabolites on the bone marrow. The hypothesis to be tested is that the lung makes a significant contribution to the bioactivation and hence the subsequent toxicity of benzene. This would include both directly inhaled benzene and that reaching the lungs via the circulation. The first objective is to compare benzene metabolism by human lung and liver with that by experimental animals. The second objective is to examine the metabolism of benzene that it inhaled and that which is systemically delivered using the isolated perfused rabbit lung (IPRL) to approximate an in vivo situation as closely as possible. The third objective is to identify the pulmonary cell types responsible for benzene metabolism.
Pulmonary and hepatic benzene metabolism will be determined using human, rat, mouse and rabbit microsomes to understand species and tissue differences. Benzene metabolism will be correlated with CYP2E1 protein and p-nitrophenol hydroxylase levels. Substrate concentration dependence studies will mimic realistic environmental exposure and those used in previous rodent studies. The IPRL will be used to compare metabolism with the benzene being delivered by inhalation or via the pulmonary vasculature. Concentration dependence will be evaluated. For the third objective, Clara and type II alveolar cells will be isolated and benzene metabolism measured over a range of concentrations.
Multiple species comparisons will determine the laboratory animal which best predicts for humans. Concentration dependence studies are critical in evaluating benzene metabolism at environmentally relevant concentrations and those used in other studies relating benzene metabolism to toxicity. Basic information will be obtained on the pulmonary cell types responsible for benzene bioactivation. Collectively, these results will define, both qualitatively and quantitatively, the importance of lung in the bioactivation of benzene and contribute to our understanding of the factors responsible for benzene toxicity.