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both the types of endpoints examined and the model systems used. Next is a description of validated in vitro assays—assays that are accepted for use in predicting effects on whole organisms. The seriousness of harm predicted by a given assay is then pointed out as an important consideration. Several annexes present information on genetic toxicology experiments, examples of validated in vitro assays, and a description of new in vitro methods that are evolving in toxicology. Finally, a spectrum of concern figure is presented to integrate the considerations discussed.

CONSIDERATIONS AND RELEVANCE TO HUMANS

A range of in vitro experimental systems is used to gain insight into the risk of adverse effects of compounds. These systems include isolated organs, isolated cells, microorganisms, subcellular organelles, and molecular entities such as enzymes, receptors, transport proteins, isolated membranes, and genes or gene fragments. A primary advantage of conducting in vitro studies is that their reductionist approach allows insight into a compound’s mechanisms of action that might be more difficult to obtain in a “whole-animal study.” The control possible with in vitro experiments enables examination of effect on the target process or structure in isolation from confounding factors. For example, control over the concentration of the chemical of interest or of one or more of its metabolites enables the interactions among chemicals or metabolites to be studied. In vitro experiments are also generally more rapid and less expensive to conduct than in vivo studies, thus in vitro studies are more likely than in vivo studies to be available for assessment of dietary supplement safety.

While the reductionist approach of in vitro studies makes them powerful and inexpensive methods useful for learning about effects and mechanisms of actions of compounds, the reductionist approach also requires careful consideration of limitations. It is important to consider the degree to which the particular in vitro system replicates the biology of the human target cells and their responses to toxic substances, as discussed below.

Another consideration is that in vitro procedures may be less informative if performed with substrate concentrations that are not comparable with those reached in vivo or if the substrate is not metabolized similarly in vitro and in vivo. It is important, for example, to consider the relationship between the compound applied directly to the in vitro system and the identity and concentration of the compound that reaches the target (e.g., tissue, receptor, subcellular component) following human ingestion of the dietary supplement ingredient. After a substance is ingested, the metabolic fate of the compound and the amount of the biologically active compound that actually reaches the target site is dependent on a multitude of processes, including absorption, distribution, metabolism, and excretion in



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