Physiologically based modeling of 1,2,4-trimethylbenzene inhalation toxicokinetics

A physiologically based toxicokinetic model was developed for inhalation ex posure of 1,2,4-trimethylbenzene (TMB) in man, The model consists of six co mpartments for TMB and one compartment for the metabolite 3,4-dimethylhippu ric acid (DMHA). Based on previous experimental findings from human exposur es to TMB, liver metabolism was divided in two pathways, one of the first o rder and one of the Michaelis-Menten type, Muscle tissue was split in two c ompartments to account for working and resting muscle tissues during bicycl e exercise, The model was used to investigate how various factors influence potential biomarkers of exposure, i.e., TMB in blood and exhaled air and D MHA in urine. Increasing the work load from rest to moderate exercise (100 W) more than doubled all biomarker levels end of shift. The effect on next morning levels was even more pronounced, illustrated by a fivefold increase in the DMHA excretion rate. Simulations of five daily 8-h exposures sugges t that biomarker levels end of shift remain fairly constant whereas the lev els prior to shift increase gradually during the week. This suggests that e nd of shift levels reflect the exposure of the same day whereas levels Frid ay morning reflect exposure during the entire working week. Simulations wit h randomly generated exposures show that the variability due to fluctuating exposure is lower next morning than end of shift, End of shift exhalation rate of TMB is more sensitive to fluctuation than TMB in venous blood and D MHA in urine. Biomarker levels for 25 ppm exposure at different sampling ti mes are given. (C) 1999 Academic Press.