Modeling of the Internal Kinetics of Benzo(a)pyrene and 3-Hydroxybenzo(a)pyrene Biomarker from Rat Data

Measurements of 3-hydroxybenzo(a)pyrene (3-OHBaP) in urine has been proposed for the biomonitoring of exposure to benzo(a)pyrene (BaP) in workers. To allow a better understanding of the toxicokinetics of BaP and its key biomarker, a multicompartment model was developed based on rat data previously obtained by this group. According to the model, iv injected BaP is rapidly distributed from blood to tissues (t(1/2) = 3.65 h), with particular affinity for tissue lipid components and liver and lung proteins. BaP is then rapidly distributed to lungs, where significant tissue uptake occurs, followed by the skin, liver, and adipose tissues. Once in liver, BaP is readily metabolized, and 3-OHBaP is formed with a t(1/2) of 3.32 h. Lung metabolism of BaP was also accounted for, but its contribution to the whole kinetics was found to be negligible. Once formed, 3-OHBaP is distributed from blood to the various organs almost as fast as the parent compound (t(1/2) = 2.26 h). In kidneys, 3-OHBaP builds up as a result of the smaller rate of 3-OHBaP urinary excretion (t(1/2) = 4.52 h) as compared with its transfer rate from blood to kidneys (t(1/2) = 27.8 min). However, overall clearance of 3-OHBaP from the body is driven by its biliary transfer from liver to the gastrointestinal tract (t(1/2) = 3.81 h). The model provides a great fit to independent sets of published data on 3-OHBaP urinary excretion time course (chi(2) = 0.019). This model proves useful in establishing the main biological determinants of the overall kinetics of these compounds.