The toxicokinetics of benzo(a)pyrene (BaP) and 3-hydroxybenzo(a)pyrene (3-OHBaP) were assessed in 36 male Sprague-Dawley rats injected intravenously with 40 micromol kg(1) of BaP to explain the reported atypical urinary excretion profile of 3-OHBaP. Blood, liver, kidney, lung, adipose tissue, skin, urine and feces were collected at t = 2, 4, 8, 16, 24, 33, 48, 72 h post-dosing. BaP and 3-OHBaP were measured by high-performance liquid chromatography/fluorescence. A biexponential elimination of BaP was observed in blood, liver, skin and kidney (t((1/2)) of 4.2-6.1 h and 12.3-14.9 h for initial and terminal phases, respectively), while a monoexponential elimination was found in adipose tissue and lung (t((1/2)) of 31.2 and 31.5 h, respectively). A biexponential elimination of 3-OHBaP was apparent in blood, liver and skin (t((1/2)) of 7.3-11.7 h and 15.6-17.8 h for initial and terminal phases, respectively), contrary to adipose tissue, lung and kidney. In adipose tissue and lung, a monophasic elimination of 3-OHBaP was observed (t((1/2)) of 27.0 h and 24.1 h, respectively). In kidney, 3-OHBaP kinetics showed a distinct pattern with an initial buildup during the first 8 h post-dosing followed by a gradual elimination (t((1/2)) of 15.6 h). In the 72-h post-treatment, 0.21 +/- 0.09% (mean +/- SD) of dose was excreted as 3-OHBaP in urine and 12.9 +/- 1.0% in feces while total BaP in feces represented 0.40 +/- 0.16% of dose. This study allowed the identification of the kidney as a retention compartment governing 3-OHBaP atypical urinary excretion.
3-hydroxybenzo(a)pyrene (3-OHBaP) in urine has been proposed as a biomarker of occupational exposure to polycyclic aromatic hydrocarbons. However, to reconstruct exposure doses in workers from biomarker measurements, a thorough knowledge of the kinetics of the benzo(a)pyrene (BaP) and 3-OHBaP given different routes of exposure is needed. A rat physiologically-based pharmacokinetic model of BaP and 3-OHBaP was built. Organs (tissues) represented as compartments were based on in vivo experimental data in rats. Tissue: blood partition coefficients, permeability coefficients, metabolism rates, excretion parameters, and absorption fractions and rates for different routes-of-entry were obtained directly from published in vivo time courses of BaP and 3-OHBaP in blood, various tissues and excreta of rats. The latter parameter values were best-fitted by least square procedures and Monte Carlo simulations. Sensitivity analyses were then carried out to ensure the stability of the model and the key parameters driving the overall modeled kinetics. This modeling pointed out critical determinants of the kinetics: (1) hepatic metabolism of BaP and 3-OHBaP elimination rate as the most sensitive parameters; (2) the strong partition of BaP in lungs compared to other tissues, followed by adipose tissues and liver; (3) the strong partition of 3-OHBaP in kidneys; (4) diffusion-limited tissue transfers of BaP in lungs and 3-OHBaP in lungs, adipose tissues and kidneys; (5) significant entero-hepatic recycling of 3-OHBaP. Very good fits to various sets of experimental data in rats from four different routes-of-entry (intravenous, oral, dermal and inhalation) were obtained with the model.
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.
A human in vivo toxicokinetic model was built to allow a better understanding of the toxicokinetics of folpet fungicide and its key ring biomarkers of exposure: phthalimide (PI), phthalamic acid (PAA) and phthalic acid (PA). Both PI and the sum of ring metabolites, expressed as PA equivalents (PAeq), may be used as biomarkers of exposure. The conceptual representation of the model was based on the analysis of the time course of these biomarkers in volunteers orally and dermally exposed to folpet. In the model, compartments were also used to represent the body burden of folpet and experimentally relevant PI, PAA and PA ring metabolites in blood and in key tissues as well as in excreta, hence urinary and feces. The time evolution of these biomarkers in each compartment of the model was then mathematically described by a system of coupled differential equations. The mathematical parameters of the model were then determined from best fits to the time courses of PI and PAeq in blood and urine of five volunteers administered orally 1 mg kg(-1) and dermally 10 mg kg(-1) of folpet. In the case of oral administration, the mean elimination half-life of PI from blood (through feces, urine or metabolism) was found to be 39.9 h as compared with 28.0 h for PAeq. In the case of a dermal application, mean elimination half-life of PI and PAeq was estimated to be 34.3 and 29.3 h, respectively. The average final fractions of administered dose recovered in urine as PI over the 0-96 h period were 0.030 and 0.002%, for oral and dermal exposure, respectively. Corresponding values for PAeq were 24.5 and 1.83%, respectively. Finally, the average clearance rate of PI from blood calculated from the oral and dermal data was 0.09 ± 0.03 and 0.13 ± 0.05 ml h(-1) while the volume of distribution was 4.30 ± 1.12 and 6.05 ± 2.22 l, respectively. It was not possible to obtain the corresponding values from PAeq data owing to the lack of blood time course data.
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