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are known to correspond to a specific functional change characteristic of an adverse health effect. It may often be appropriate to use in vitro data as hypothesis generators, as potential indicators of harmful health effects, or as information about biological plausibility or mechanism, rather than as standalone demonstrated indicators that in themselves indicate risk. However, some types of in vitro assays should be considered validated as predictors of possible harm, and thus when carefully conducted and interpreted, will provide valuable information beyond simply reinforcing observations from other categories of data or generating hypotheses. In vitro assays warrant attention and are appropriate to use as standalone indicators of risk to human health when the relationship between the results of an in vitro assay and actual clinical or animal outcomes has been demonstrated, thus validating the predictive value of the assay.

A number of validated in vitro tests are in standard use for regulated materials and are often required for premarket approval by a regulatory authority. These form an important established battery of tests that are useful in predicting possible adverse effects. Although the regulatory situation is such that completion of these or other in vitro tests is not required for dietary supplement ingredients, the scientific value of these assays in predicting adverse effects in humans is as valuable in assessing the safety of dietary supplements as it is in assessing the safety of other substances. For example, specific types of in vitro tests are used by the Environmental Protection Agency (EPA) and the Food and Drug Administration (FDA) to identify potential pesticides and food additives that may lead to adverse effects (see Annex 7-2). In summary, it is recommended that in vitro assays—such as those contained in the Redbook (OFAS, 2001, 2003); Protection of Environment (40 C.F.R. § 150–189 [1998]); and the Consumer Product Safety Commission and its subacts, the Federal Hazardous Substances Act (15 U.S.C. § 1261–1278 [1960]) and the Labeling of Hazardous Art Materials Act (15 U.S.C. § 1277 [1988])—all be considered, among others, as important validated assays in the prediction of possible adverse effects in humans.

Assays used by regulatory bodies are by no means the only assays or in vitro observations that should be considered as validated and thus independent predictors of risk. Other specific assays, such as certain receptors or ion channel assays, should also be considered validated. The important concept is that for an assay to stand alone as a predictor of risk, a connection between the observed biological effect and an adverse effect needs to have been made. (In Chapter 10, this concept is illustrated by the need for linkages between observed biological effects and adverse health effects.)

In addition to the types of in vitro effects considered validated, other in vitro information is also valuable for assessing biological plausibility of concerns raised by other observations, such as observations of adverse



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