Benzene toxicokinetics in humans: exposure of bone marrow to metabolites.

A three compartment physiologically based toxicokinetic model was fitted to human data on benzene disposition. Two separate groups of model parameter derivations were obtained, depending on which data sets were being fitted. The model was then used to simulate five environmental or occupational exposures. Predicted values of the total bone marrow exposure to benzene and cumulative quantity of metabolites produced by the bone marrow were generated for each scenario. The relation between cumulative quantity of metabolites produced by the bone marrow and continuous benzene exposure was also investigated in detail for simulated inhalation exposure concentrations ranging from 0.0039 ppm to 150 ppm. At the level of environmental exposures, no dose rate effect was found for either model. The occupational exposures led to only slight dose rate effects. A 32 ppm exposure for 15 minutes predicted consistently higher values than a 1 ppm exposure for eight hours for the total exposure of bone marrow to benzene and the cumulative quantity of metabolites produced by the bone marrow. The general relation between the cumulative quantity of metabolites produced by the bone marrow and the inhalation concentration of benzene is not linear. An inflection point exists in some cases leading to a slightly S shaped curve. At environmental levels (0.0039-10 ppm) the curve bends upward, and it saturates at high experimental exposures (greater than 100 ppm).