Physiologically Based Pharmacokinetic Modeling of Cyclohexane as a Tool for Integrating Animal and Human Test Data

This report describes a physiologically based pharmacokinetic model for cyclohexane and its use in comparing internal doses in rats and volunteers following inhalation exposures. Parameters describing saturable metabolism of cyclohexane are measured in rats and used along with experimentally determined partition coefficients. The model is evaluated by comparing predicted blood and brain concentrations to data from studies in rats and then allometrically scaling the results to humans. Levels of cyclohexane in blood and exhaled air are measured in human volunteers and compared with model values. The model predicts that exposure of volunteers to cyclohexane at levels of 4100 mg/m3 (∼1200 ppm) will result in brain levels similar to those in rats exposed to 8000 mg/m3 (the no-effect level for acute central nervous system effects). There are no acute central nervous system effects in humans exposed to 860 mg/m3, consistent with model predictions that current occupational exposure levels for cyclohexane protect against acute central nervous system effects.