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

Abstract

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 (t₁/₂ = 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 t₁/₂ 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 (t₁/₂ = 2.26 h). In kidneys, 3-OHBaP builds up as a result of the smaller rate of 3-OHBaP urinary excretion (t₁/₂ = 4.52 h) as compared with its transfer rate from blood to kidneys (t₁/₂ = 27.8 min). However, overall clearance of 3-OHBaP from the body is driven by its biliary transfer from liver to the gastrointestinal tract (t₁/₂ = 3.81 h). The model provides a great fit to independent sets of published data on 3-OHBaP urinary excretion time course (χ² = 0.019). This model proves useful in establishing the main biological determinants of the overall kinetics of these compounds.

Comparison of toxicogenomics and traditional approaches to inform mode of action and points of departure in human health risk assessment of benzo[a]pyrene in drinking water

“…Extrapolation of a PBPK model for the pharmacokinetics of pyrene (Haddad et al, 1998) to BaP yielded inconsistent results. Heredia-Ortiz et al (2011) presented an alternative toxicokinetic compartmental model to describe the pharmacokinetics of BaP in rats. While the model is consistent with experimental data on rats, the model uses rate constants instead of physiological parameters.…”

Use of Physiologically-Based Pharmacokinetic Modeling to Simulate the Profiles of 3-Hydroxybenzo(a)pyrene in Workers Exposed to Polycyclic Aromatic Hydrocarbons

“…Our model has also shown that, a few hours after exposure, the urinary excretion profiles are governed by the slow release of BaP from organs retaining the parent compound, namely adipose tissues and lungs. A similar observation can be drawn from a toxicokinetic model previously developed by our team [20]. Also, according to this PBPK modeling and prior toxicokinetic modeling [20] based on observed time-course data in rats [35], [40], the urinary excretion of 3-OHBaP is delayed with respect to blood profiles.…”

“…A similar observation can be drawn from a toxicokinetic model previously developed by our team [20]. Also, according to this PBPK modeling and prior toxicokinetic modeling [20] based on observed time-course data in rats [35], [40], the urinary excretion of 3-OHBaP is delayed with respect to blood profiles. Our modeling assumed that the major reason for such a delay was the relatively slow transfer of 3-OHBaP occurring in the kidneys and a possible interaction of 3-OHBaP in the bladder.…”

“…This elimination rate is also influenced by the clearance of each organ. However, only the biological process contributing the most to the observed time-courses needed a species-specific adjustment, thus in our case the amounts of BaP in adipose tissues (according to Heredia-Ortiz et al [20]) (see Table 1). Given the small number of parameters, no sensitivity analysis was carried out for the single compartment model.…”

“…Biologically-based toxicokinetic models allowing to relate the time course of a biomarker of exposure to the time-varying amounts in the body and doses per unit of time have been used by our group to reconstruct exposure in workers exposed to methanol and pesticides [16]–[19]. Recently, such type of toxicokinetic model has been developed to describe the kinetics of BaP and its 3-OHBaP biomarker of exposure in animals and humans [20]. Other types of kinetic models include physiologically-based pharmacokinetic (PBPK) models.…”