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other well-characterized biological differences may lessen or eliminate concerns about human toxicity. Clues to such differences may arise when findings in one species of animal are not observed, under similar dosing conditions, in a second species. Such an observation is, however, only a clue, and cannot be taken by itself as evidence of irrelevance to humans. Rather, data that can be used to explain species differences are necessary to draw strong inferences regarding relevance or lack thereof.

Bioavailability, Pharmacokinetics and Knowledge of Absorption, Metabolism, Excretion, and Distribution Processes

When comparing the quantified ingested dose resulting in animal adverse effects with information about a human ingested dose, it is useful to consider the relationship between the amount ingested and the amount of the substance or its metabolites that reach the active site1 (usually indicated by the concentration of unbound compound in the blood, and described in terms of bioavailability [see Chapter 3]). Pharmacokinetic processes, such as absorption, metabolism, excretion, and distribution, affect how much of the ingested substance actually reaches sites of action in the body. Differences in the pharmacokinetic processes of humans and experimental animals can lead to differences in the plasma concentration of active constituents that result from a given intake amount. Evaluating possible pharmacokinetic differences between experimental animals and humans requires some knowledge of the comparative absorption, distribution, metabolism, and excretion of the test substance in animals and in humans (Klaassen, 2001) and a judgment regarding the degree to which any observed differences in these measures are sufficient to discount animal test findings. The reality is that quantitative information about how these pharmacokinetic variables should appropriately impact the extrapolation of safety information from animals to humans is not available for many substances, especially dietary supplement ingredients. Thus this type of evaluation should be undertaken by experts on a case-by-case basis. When detailed understanding of absorption, distribution, biotransformation, or excretion in experimental animals or humans is not available to make a comparison possible, it is appropriate to assume the most sensitive experimental animal studies are relevant to humans.

Linear Versus Nonlinear Dose-Response Assumption

Mechanistic or mode-of-action information may be used to improve the risk assessment by providing information about the relationship be-

1  

See also discussion in Chapter 8.



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