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Dietary Supplements: A Framework for Evaluating Safety
effects in animals or humans. The assessment of biological plausibility becomes an issue when interpreting data and trying to predict the likelihood of causal relationships (see Chapter 10). While it is not necessary to establish a rational mechanism of harm to conclude that an ingredient poses an unreasonable risk, it is nonetheless valuable to identify possible mechanisms that explain the totality of the data. Many in vitro studies can be useful for this purpose.
SERIOUSNESS OF HARM PREDICTED BY THE ASSAY
In addition to considering the correlation of the particular in vitro assay with a particular adverse health outcome, it is of utmost importance to consider the seriousness of the outcome when evaluating the level of concern warranted by results of in vitro studies. Assays that warrant the most attention are those that predict biological effects/outcomes associated with toxicological manifestations, pathologies, or effects that could reasonably be hypothesized to lead to serious risks. This concept is analogous to Table 5-1, which categorizes the relative seriousness of various types of effects observed in animals.
There is no quantitative method of assigning a weight to the outcome of each in vitro experiment and imputing an appropriate level of concern for public health risk from such data. Instead, it is important for experts to reach a judgment about the in vitro results based on the seriousness of the effect predicted, the validity of the assay in identifying substances that cause a particular adverse effect, the quality of the individual studies, and the consistency among the collection of studies. Considerations on study quality discussed in the human and the animal chapters (Chapters 4 and 5) apply to in vitro systems as well. Considerations include the strength of the association, its reproducibility in the same and corresponding systems, the specificity of the findings for both cause and effect, and the coherence of the evidence—all of which give more confidence that the findings are meaningful.
When considering the information, it will be helpful to answer the following questions to decide how much concern for public health is warranted by the in vitro evidence:
Is the in vitro test validated or commonly used to predict a serious adverse effect? For example, assays used in regulatory situations to predict possible carcinogenic effects are considered as such.
Is the assay considered predictive of a particular adverse effect?