Target-related toxicity tissue distribution

Use of tissue distribution to evaluate target-related toxicity... 

Thus, vivo and Jji vitro studies demonstrate that the age-related differences in kidney alkylation and toxicity by IPO in the mouse are due to changes in renal metabolism rather than changes in the tissue distribution of the parent compound. Histologic evaluation of lung, liver and kidney from the rat and hamster show no age-related differences in target organ alkylation or toxicity. 

As illustrated in the previous chapter, the human body can be exposed to a variety of toxicants that may be present in various environmental media such as air, soil, water, or food. However, just simply being exposed to these hazardous chemicals does not necessarily translate into a toxicological response. The mammalian body has several inherent defense mechanisms and membrane barriers that tend to prevent the entry or absorption and distribution of these toxicants once an exposure event has occurred. However, if the toxicant is readily absorbed into the body, there are still other anatomical and physiological barriers that may prevent distribution to the target tissue to elicit a toxic response. As the toxicological response is often related to the exposed dose, interactions between the toxicant and the body s barriers and defense mechanisms will have an effect on toxicant movement in the body, and ultimately modulate the rate and extent of toxicant absorption and distribution to the target tissue. 

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. 

TCDD and related chemicals, as well as the pharmacokinetics of dioxins in experimental animals. For CDDs, toxicity and toxicokinetics cannot be dealt with separately. Based on results from research in these fields, it has become apparent that the comparison of responses from animals to humans (or even between animal species) should be done on the basis of body-burden or target-tissue dose, rather than on the basis of administered dose. By doing so, species-specific toxicokinetic considerations such as dose-dependent distribution, the existence of tissue-specific sequestering chemical entities (i.e., CYP1A2), and body composition (i.e., percent fat) can be taken into account. A discussion of relationships between administered dose, body burden, and biological responses is presented below. 

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