POPULATION TOXICOKINETICS OF BENZENE

In assessing the distribution and metabolism of toxic compounds in the body, measurements are not always feasible for ethical or technical r easons. Computer modeling offers a reasonable alternative, but the var iability and complexity of biological systems pose unique challenges i n model building and adjustment. Recent tools from population pharmaco kinetics, Bayesian statistical inference, and physiological modeling c an be brought together to solve these problems. As an example, we mode led the distribution and metabolism of benzene in humans. We derive st atistical distributions for the parameters of a physiological model of benzene, on the basis of existing data. The model adequately fits bot h prior physiological information and experimental data. An estimate o f the relationship between benzene exposure (up to 10 ppm) and fractio n metabolized in the bone marrow is obtained and is shown to be linear for the subjects studied. Our median population estimate for the frac tion of benzene metabolized, independent of exposure levels, is 52% (9 0% confidence interval, 47-67%). At levels approaching occupational in halation exposure (continuous 1 ppm exposure), the estimated quantity metabolized in the bone marrow ranges from 2 to 40 mg/day.