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. 2012:2012:359471.
doi: 10.1155/2012/359471. Epub 2012 May 9.

Physiologically based toxicokinetic modelling as a tool to support risk assessment: three case studies

Hans Mielke  1 , Ursula Gundert-Remy
Affiliations

Physiologically based toxicokinetic modelling as a tool to support risk assessment: three case studies

Hans Mielke et al. J Toxicol. 2012.

Abstract

In this contribution we present three case studies of physiologically based toxicokinetic (PBTK) modelling in regulatory risk assessment. (1) Age-dependent lower enzyme expression in the newborn leads to bisphenol A (BPA) blood levels which are near the levels of the tolerated daily intake (TDI) at the oral exposure as calculated by EFSA. (2) Dermal exposure of BPA by receipts, car park tickets, and so forth, contribute to the exposure towards BPA. However, at the present levels of dermal exposure there is no risk for the adult. (3) Dermal exposure towards coumarin via cosmetic products leads to external exposures of two-fold the TDI. PBTK modeling helped to identify liver peak concentration as the metric for liver toxicity. After dermal exposure of twice the TDI, the liver peak concentration was lower than that present after oral exposure with the TDI dose. In the presented cases, PBTK modeling was useful to reach scientifically sound regulatory decisions.

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Figures

Figure 1
Figure 1
BPA: simulation results oral versus dermal route. Humans are exposed towards BPA on the oral and on the dermal routes.
Figure 2
Figure 2
Exploration of which toxicokinetic metric is toxicodynamically relevant. Severity grade of liver toxicity (points) in relation to (a) the peak concentration in the liver (μg/g liver tissue) for coumarin in rat. (b) AUC in the liver (μg/g × h) for coumarin in rat. A toxicokinetic model has been constructed for the rat, and C max⁡ and AUC were simulated with doses and duration of exposure taken from published studies (n = 11). The toxicological endpoint in the studies was liver toxicity the degree of which differed, and we graded the toxicity in a scale from 0 to 4. C max⁡ in the liver (liver peak concentration) was better correlated to liver toxicity than AUC in the liver indicating that it C max⁡ in the liver is the toxicologically relevant toxicokinetic metric.
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