Review Article
Physiologically Based Toxicokinetic Modelling as a Tool to Support Risk Assessment: Three Case Studies
Table 2
BPA: Simulation results comparing of oral and dermal exposure. Results are given as (pg/g) and AUC (pg/g × h) in blood, liver, and kidney after dermal (extent of absorption 60% of the dose), and oral (extent of absorption 90% of the dose) administration. The external oral doses are identical with the external dermal dose (0.97 μg/kg/d), a dose estimated by FAO/WHO (4.2 g/kg/d) as the upper level estimate and a dose at the tolerated daily intake (TDI) (50 g/kg/d). BPA undergoes first pass in the liver. The first pass in the liver produces a lower concentration in the systemic circulation ( and AUC in blood) compared to values after the dermal administration despite identical doses and a lower extent of absorption through skin as compared to the oral absorption. In contrast, and AUC in the liver are higher after oral as compared to the dermal exposure. Dermal dose (μg/kg/d) of BPA which corresponds to the concentration difference between blood concentrations published by Sajiki et al., 1999 [25] and by Padmanabhan et al., 2008 [26] and the estimated oral dose by FAO/WHO, 2010. The blood concentration of BPA in a person who has ingested BPA at the upper level of oral exposure (4.2 μg/kg/d) as calculated by FAO/WHO is 70.6 pg/mL. Sajiki et al., 1999 [25] has measured a mean blood concentration of 330 pg/mL and Padmanabhan et al., 2008 [26], a mean blood concentration of 5900 pg/mL. We calculated the difference of the blood concentrations measured by Sajiki et al. and by Padmanabhan et al. [25, 26] and the modelled blood concentration caused by an oral dose of 4.2 μg/kg/d. We then modelled the dermal dose which would be necessary to produce the concentration corresponding to the difference between measured and modelled concentration. It can be seen that this dose (9.4 and 211.8 μg/kg/d, resp.) is 10 to 200 fold higher than the experimentally measured dose of 0.97 μg/kg/d [27].
| (a) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
*Blood concentration in the systemic circulation, not in the portal vein. In case of the oral route of administration, concentration in the portal vein is higher than concentration in the systemic circulation. **Dermal dose given at once, whereas the oral doses are given in three divided portions. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| (b) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||