BENZENE TOXICOKINETICS IN HUMANS - EXPOSURE OF BONE-MARROW TO METABOLITES

A three compartment physiologically based toxicokinetic model was fitt ed 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 e xposure 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 co ntinuous benzene exposure was also investigated in detail for simulate d inhalation exposure concentrations ranging from 0.0039 ppm to 150 pp m. At the level of environmental exposures, no dose rate effect was fo und for either model. The occupational exposures led to only slight do se rate effects. A 32 ppm exposure for 15 minutes predicted consistent ly higher values than a 1 ppm exposure for eight hours for the total e xposure of bone marrow to benzene and the cumulative quantity of metab olites produced by the bone marrow. The general relation between the c umulative 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 environ mental levels (0.0039-10 ppm) the curve bends upward, and it saturates at high experimental exposures (greater than 100 ppm).