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Dose to Dose

PBPK permits reasonable extrapolation from one dose to another, if adequate information on physicochemical properties, physiology, pharmacology, and biochemistry is available. That is not often the case, with less being known as one moves along the list from physiochemical properties to biochemistry; however, PBPK models clearly reveal what data they require and thus what experiments will be needed to make them useful. 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. Despite those difficulties, there are many examples in the literature where useful PBPK analyses have been undertaken. Although PBPK analyses do not always directly address the question of pharmacodynamics (how the biologically effective dose to a critical target tissue is related to toxic response in that tissue), such analyses might provide insight pertinent to this question.

Route to Route

Two broad categories of route-specific toxicity need to be considered: "noncorrosive" and "corrosive." In the former, a chemical enters the body by some route and exerts its effect in the interior of the body; it must enter the blood circulation before it has its effect. In the latter, a very active chemical can have a direct effect at the point of entry, such as high levels of formaldehyde in the case of the rat, nitric acid on skin, or ethylene dibromide at the tip of a gavage tube. Some compounds, such as ethylene dibromide, can be both corrosive and noncorrosive.

Most toxicants are noncorrosive, and knowledge of relevant physiology and pharmacology can permit extrapolation between routes of exposure, because the important information is the concentration in the blood and the transport to and uptake at the site of action. There could still be route-to-route differences, e.g., if the peak concentration after exposure determines toxicity. For example, absorption might be faster (and thus the peak higher) for intravenous than for oral exposure. PBPK models are useful, because they permit estimation of peak concentrations.

Species to Species

Species-to-species extrapolation is one of the most useful aspects of PBPK, because all mammals have the same macrocirculatory anatomy and much is known about the comparative dimensions of their physiologic characteristics—organ volumes, blood flow rates, some clearances, etc. The basic data are usual-



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