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10 Scientific Principles for Integrating and Evaluating the Available Data
Pages 253-268

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From page 253...
... The first section of this chapter explains why it is not possible to use a formulaic or algorithmic approach to integrate and evaluate the data. The next section describes how the systematic integration of knowledge and judgment can be used to assess dietary supplements for risk in a practical, informative, and transparent manner using causal models.
From page 254...
... It is also not appropriate to develop a hierarchical approach to considering the different types of data -- human data, animal data, in vitro data, or information about related substances -- for various reasons. In part, such an approach is not feasible because of limitations in the quality of the data and what different types of studies can reveal, but these limitations can be overcome with other types of data.
From page 255...
... INTEGRATING INFORMATION GUIDING PRINCIPLE: Integration of data across different cat egories of information and types of study design can enhance bio logical plausibility and identify consistencies, leading to conclu sions regarding levels of concern for an adverse event that may be associated with use of a dietary supplement ingredient. Individual pieces of information from any one of the categories of information (human, in vitro, animal, or related substances data)
From page 256...
... Figure 10-2 illustrates two possible scenarios of conclusive animal data. The first diagram illustrates a situation where the dietary supplement ingredient is known to 3 The term "biological effects" does not necessarily mean health effects.
From page 257...
... ingredient B C FIGURE 10-1 Illustration of causal model concept for conclusive human data. A solid arrow (A, B, or C)
From page 258...
... FIGURE 10-4 Illustration of causal model concept for conclusive information about "functionally related" substances. The solid arrow from the ingredient to the biological effect represents an association between the two as evidenced by human, animal, or in vitro data.
From page 259...
... The fact that a related substance causes the adverse health effect through the biological effect provides a path of arrows between the dietary supplement ingredient and the adverse heath effect. Evidence from all types of study designs may form linkages to aid in determining the extent of association between dietary supplement exposure and adverse health outcomes.
From page 260...
... biological compounds Biological eff Biological eff causal strong different arrows a the of very X y Dashed X X y y data across Y Dietar redient data data related supplement ing Dietar redient Dietar redient supplement ing supplement ing vitro Human about substances Animal In Illustration effect independently integrated 10-5 not adverse are when and FIGURE that that, X
From page 261...
... substance Integ Illustration effect. the vitro together illustrates in health 10-6 evidence available suggest that related supplement a w is taken Sa palmetto figure data some adverse biological data FIGURE sidering The studies a dietary mal indicates also Finally, the of male in male in in in utero ects utero genitalia ects genitalia Def Def - ide 5- - 5 reductase inhibition 5 substances reductase inhibition reductase inhibition Finaster related about data w w data data Sa Sa palmetto palmetto vitro Human Animal In
From page 262...
... Figures 10-5 and 10-6 show that summing, or synthesizing, data addressing different linkages forms a more complete causal evidence model and can provide the biological plausibility needed to establish the association between a dietary supplement and an adverse event. In summary, causal models are useful when individual pieces of evidence are weak and are of different types or when they do not clearly illustrate a relationship, when viewed individually, as may often be the case with dietary supplement ingredients.
From page 263...
... These concepts are reflected in the manner in which data were analyzed in the prototype monographs released with this report and summarized in Appendixes D through K The amount of product ingested, route of exposure, and the processing and composition as well as the formulation of the ingredient used in each study, were all taken into consideration in determining the relevance of datasets for use in evaluating the level of concern for safety of the dietary supplement ingredients reviewed.
From page 264...
... This is because the amount of constituent ingested by humans may vary significantly, as discussed above, and because there may be consistency between the types of adverse effects observed following ingestion of these elevated amounts and lesser but similar effects observed following ingestion of lower amounts typically consumed as a dietary supplement. Alternatively, the effects seen at these higher levels may provide biological plausibility for less serious effects observed following consumption of lower amounts.
From page 265...
... Another possible explanation for apparent inconsistencies in the observation of adverse effects may be differences in the quality of the reports. Important aspects of studies from each category of data, including human, animal, and in vitro studies, have been discussed in detail in Chapters 4 through 7.
From page 266...
... In general, if there is scientifically based evidence from human studies indicating that a concern for safety exists, then the lack of adverse events in animal studies, in vitro studies, or even other human studies cannot be used to overrule or disregard the evidence of harm. The absence of adverse findings in animal studies, no matter how well designed, does not prove that pathological effects will not occur in humans; thus, the absence of an effect or observation in animals cannot mitigate concern raised by human data.
From page 267...
... While it is unusual in the dietary supplement field at present to have such detailed knowledge, occasionally an understanding of the pathway responsible for the toxicity can mitigate the extrapolation to humans of concerns raised in animal studies. PROOF OF HARM For a number of dietary supplements ingredients, decisions regarding safety must be made despite sparse data and shortcomings in the studies that are available.
From page 268...
... Rather than a quantitative, probabilistic assessment of risk, which is preferable and often possible when data about a chemical are substantial or at least include standard toxicology tests, it may be prudent or necessary to make a qualitative determination by using judgment and scientific inference to consider the limited data. In summary, to evaluate dietary supplements under DSHEA, it is necessary to determine only if an "unreasonable or significant risk" exists, not to have complete evidence that a dietary supplement causes a serious adverse event.


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