Physiologically Based Toxicokinetic Modelling as a Tool to Support Risk Assessment: Three Case Studies
Table 1
BPA steady state concentration in blood after oral exposure by 11 g/kg/day in bottle fed newborns. The steady state concentration (SSC) is compared to a steady state concentration in an adult exposed to 11 g/kg/day and to the 50 g/kg/day on the oral route. It can be seen that the steady state concentration in the newborn is three-fold higher than in the adult due to the fact that the metabolism of BPA by glucuronidation is impaired in the newborn. However, the SSC in the newborn does not exceed the SSC of an oral dose of 50 g/kg/d. The oral dose of 50 g/kg/d equals the tolerated daily intake derived from animal studies. It is thought to be a level without adversely influencing the health calculated for the population older than 3 months. The SSC of 50 g/kg/d has been simulated with the model parameters of an adult. Relative contribution of the two pathways in the metabolism of BPA in relation to age (and related to age extent of impaired glucuronide conjugation). 85% of a dose of BPA is metabolized to the glucuronide conjugate to and the remaining 15% to the sulfate conjugate in the adult. The enzyme which mediates the conjugation to BPA-glucuronide (uridine diphosphate-glucuronosyltransferase 2B15, UTG 2B15) is expressed at birth to only 10% of the adult level. The expression levels reach adult levels by the age of 1.5 years. The relative percentage of the glucuronidation pathway depends on the expression level of UTG 2B15. In the newborn only 36% of the absorbed dose is metabolized via glucuronidation, whereas 64% of the absorbed dose is sulfated.
(a)
Oral exposure (μg/kg/day)
Steady state concentration (SSC) (ng/mL)
Percentage of TDI SSC
SSC newborn/SSC adult at 11 μg/kg/day
Newborn (bottle-fed)
11 (EFSA, 2006)
0.096
73.8
3.3
Adult
11 (hypothetical)
0.029
22.3
—
Adult
50 (TDI)
0.13
100
—
(b)
Sulfate conjugate (percentage of the absorbed dose)
Glucuronide conjugate (percentage of the absorbed dose)
