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Guiding Principles for Evaluating Data to Determine Unreasonable Risk

  • General principles

    • Absence of evidence of risk does not indicate that there is no risk.

    • Proof of causality or proof of harm is not necessary to determine unreasonable or significant risk.

    • Integration of data across different categories of information and types of study design can enhance biological plausibility and identify consistencies, leading to conclusions regarding levels of concern for an adverse event that may be associated with use of a dietary supplement.

  • Human data

    • A credible report or study finding of a serious adverse event in humans raises concern about the ingredient’s safety and requires further information gathering and evaluation; final judgment, however, will require consideration of the totality of the evidence.

    • Historical use should not be used as prima facie evidence that the ingredient does not cause harm.

    • Considerable weight can be given to a lack of adverse events in large, high-quality, randomized clinical trials or epidemiological studies that are adequately powered and designed to detect adverse effects.

  • Animal data

    • Even in the absence of information on adverse events in humans, evidence of harm from animal studies is often indicative of potential harm to humans.

  • Related substances

    • Scientific evidence for risk can be obtained by considering if the plant constituents are compounds with established toxicity, are closely related in structure to compounds with established toxicity, or the plant source of the botanical dietary supplement itself is a toxic plant or is taxonomically related to a known toxic plant.

    • Supplement ingredients that are endogenous substances or that may be related to endogenous substances should be evaluated to determine if their activities are likely to lead to serious effects. Considerations should include the substance’s ability to raise the steady-state concentration of biologically active metabolites in tissues and whether the effect of such increases would be linked to a serious health effect.

  • In vitro data

    • Validateda in vitro studies can stand alone as independent indicators of risk to human health if a comparable exposure is attained in humans and the in vitro effects correlate with a specific adverse health effect in humans or animals.


In this report, in vitro assays are considered validated when their results have been proven to predict a specific effect in animals and/or humans with reasonable certainty (not necessarily universally accepted or without detractors).

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