Extrapolation across Doses Routes of Exposure and Species

PBPK modeling can play an essential role in three common types of extrapolation used in classical toxicology: dose to dose (usually high dose in animals to low dose for realistic exposure scenarios), route to route (e.g., ingestion vs. inhalation), and species to species (animal or cell culture to human). Each of these types of extrapolation is described in some detail below.

Dose to Dose PBPK modeling permits reasonable extrapolation from one dose to another, if adequate information on physiology, physicochemical properties, and biochemistry is available. If the dynamic processes modeled by the PBPK approach are all directly proportional to administered concentrations, then the extrapolation can be relatively straightforward. However, this is not often the case, especially at higher doses, where saturation of metabolic or clearance processes can occur [14,19]. Further causes of nonlinearity of chemical kinetics include the induction and inhibition of metabolic enzymes [14]. Despite these difficulties successful applications of dose extrapolation using PBPK models for many chemicals have been published [20,21], and several recent studies have demonstrated the usefulness of PBPK modeling for the investigation of the chemical kinetics of lipophilic compounds at different dosage regimens [22,23].

Route to Route PBPK models have been used for route-to-route extrapolation for specific chemicals and systems, and have been shown to produce accurate predictions in many cases [24]. By assuming that the relationship between applied dose and tissue dose of the xenobiotic of interest is the same, regardless of the exposure route, route-to-route extrapolations may be performed by the addition of intake terms to the governing mass balance equations that represent each exposure pathway or mechanism. The uncertainty associated with this approach can arise from the first-pass effect as well as variations in rates and extent of absorption and metabolism from one route to another [25]. However, by accounting for these route-specific processes, PBPK models can be used to conduct route-to-route extrapolations [26].

Species to Species PBPK modeling is a highly appropriate approach for species-to-species extrapolation because all mammals have the same "compartment-scale" circulatory anatomy, and much is known about the comparative dimensions of their blood flow rates, organ volumes, and clearances. In order to conduct such an extrapolation, estimates of physiological parameters, partition coefficients, and metabolic rate constants must be obtained for the species of interest [14]. Although several methods to obtain these parameters were described earlier, it is worth considering this issue in the context of species-to-species extrapolation. It has been observed that many anatomical and physiological variables can be empirically correlated to the body mass of a species [27,28], and that the physiological function per unit of organ or body mass decreases as the size of the animal increases [29]. For those parameters used in the description of metabolism, the situation is generally much more complex. This is because there might be qualitative differences between species, such as the presence or absence of a given enzyme that would result in a (potentially dose-dependent) difference in metabolic capacity. Some correlations for metabolic rate constants in terms of animal body weight have been proposed for chemicals that have a high affinity for metabolizing enzymes [14], but a more generally applicable method has yet to be introduced.

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