Xenobiotics exposure routes

For all these reasons, PBPK models are and will continue to be increasingly used in toxicology. This is especially true in risk assessment studies since better definition of the internal tissue dose, may contribute to reduce the uncertainty associated with extrapolation to human beings of responses observed in animal toxicity studies in which animals usually receive high doses of xenobiotics by routes often different from the one(s) anticipated in human exposures. 

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],... 

The explanation of the pharmacokinetics or toxicokinetics involved in absorption, distribution, and elimination processes is a highly specialized branch of toxicology, and is beyond the scope of this chapter. However, here we introduce a few basic concepts that are related to the several transport rate processes that we described earlier in this chapter. Toxicokinetics is an extension of pharmacokinetics in that these studies are conducted at higher doses than pharmacokinetic studies and the principles of pharmacokinetics are applied to xenobiotics. In addition these studies are essential to provide information on the fate of the xenobiotic following exposure by a define route. This information is essential if one is to adequately interpret the dose-response relationship in the risk assessment process. In recent years these toxicokinetic data from laboratory animals have started to be utilized in physiologically based pharmacokinetic (PBPK) models to help extrapolations to low-dose exposures in humans. The ultimate aim in all of these analyses is to provide an estimate of tissue concentrations at the target site associated with the toxicity. 

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