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5 Categories of Scientific Evidence--Animal Data
Pages 156-174

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From page 156...
... Information about animal exposure to dietary supplement ingredients may be in the form of formal studies such as traditional toxicity studies, safety pharmacology data, or observations from clinical veterinary medicine. Because dietary supplements are not required to undergo formal animal toxicity testing before marketing, extensive toxicity studies common to drugs and other substances are not likely to exist, but limited amounts of animal data are available in the scientific literature for a number of dietary supplement ingredients.
From page 157...
... Unless there is scientific evidence that raises significant doubt regarding the relevance of specific toxicity findings to humans, it is prudent and scientifically appropriate to consider animal studies relevant in evaluating potential human toxicity, especially in the many cases of dietary supplement ingredients where sufficient human data are not available. Similar positions on the relevance of animal data to human health have been supported by other committees of the National Academies, as well as by other organizations in the United States and internationally (NRC, 1994, 2001; NTP, 2002; WHO, 1999)
From page 158...
... provide different information relevant to considering the potential toxic properties of a dietary supplement ingredient and can be classified as either traditional toxicology studies or as safety pharmacology studies. Traditional Toxicology Studies FDA's Redbook describes several toxicology studies that are typically conducted in assessing the safety of food additives and other ingested substances (OFAS, 2001, 2003)
From page 159...
... Safety Pharmacology Studies Safety pharmacology studies are conducted in various animal species to detect alterations in physiological functions at dosages lower than those used to elicit overt toxic effects detected in animal toxicity protocols. Guidance for conducting safety pharmacology studies for human pharmaceuticals is provided by FDA, which defines them as "those studies that investigate the potential undesirable pharmacodynamic effects of a substance on physiological functions in relation to exposure in the therapeutic range and above" (ICH/FDA, 2001)
From page 160...
... Owners of domestic animals, which are not only restricted to cats and dogs but may also include individual cattle, sheep, goats, and horses, frequently report only acute toxicity, typically resulting from poisoning by a house or garden plant. Serious adverse events reported in animals, such as livestock, may also provide helpful information.
From page 161...
... CONSIDERATIONS FOR ASSESSING ANIMAL DATA Human Versus Animal Dose The degree of potential human risk is a function of the nature and seriousness of the observed toxicity and the dose at which it occurs in animals relative to the expected human intake of the substance. One of the unique and powerful approaches of animal testing is the administration of high amounts of a substance over a short time period.
From page 162...
... and a judgment regarding the degree to which any observed differences in these measures are sufficient to discount animal test findings. The reality is that quantitative information about how these pharmacokinetic variables should appropriately impact the extrapolation of safety information from animals to humans is not available for many substances, especially dietary supplement ingredients.
From page 163...
... Such findings, or others that suggest irrelevance of the particular animal study evidence to humans, should be used to reach conclusions about possible human toxicity only after careful review. In the absence of specific evidence that certain animal study findings are irrelevant to humans, animal evidence should be used to evaluate potential human risk.
From page 164...
... Lack of Adverse Effects in Animals As with any type of scientific study in which an effect is not observed, it is important to remember that a lack of observed or reported detrimental effects in an animal study is not adequate evidence that a particular substance is "safe" to humans.2 The sensitivity of animal experiments in detecting particular effects is of utmost importance when extrapolating from animal studies to humans. Use of animal data to mitigate concerns raised by other data is appropriate only if animal studies are sensitive enough to detect adverse effects if they occur.
From page 165...
... WHEN DO ANIMAL DATA WARRANT CONSIDERATION AS AN INDICATOR OF SERIOUS RISK TO HUMAN HEALTH? Pathophysiological Effects in Animals That Raise the Most Concern Animal toxicity outcomes with clearly definable pathological changes are more compelling with regard to their relevance to humans than are outcomes in which only physiological or biochemical abnormalities are found.
From page 166...
... · Reduced body weight gain · Body weight/organ weight ratios · Reduced food consumption · Enzyme changes, other biochemical and toxicity biomarker alterations unaccompanied by histological changes · Reversible degenerative changes regardless of the presence of high-quality human data suggesting no acute toxicity. This is because human exposure may need to be prolonged before such toxicities would be detected.
From page 167...
... Issues confronting FDA in regulating dietary supplements are not exactly analogous to those that arise in the premarketing approvals of other substances such as food additives, for which protocols for using animal data to establish safety have been developed. The traditional use of animal toxicity data to establish acceptable exposures has imbedded within it an element of caution -- animal toxicity findings are used without significant question regarding the predictive power of specific findings for humans, and uncertainty factors are used to ensure safety.
From page 168...
... The follow ing assumptions have long been applied in making those safety evaluations: 1. The most sensitive indicator of adverse effects is selected from the entire body of reported animal data, relying on quality of the data and/or weight of the evidence.a 2.
From page 169...
... . The risk assessment model proposed in this chapter for using animal data is to consider that the data are a means to integrate information about the seriousness of the observed animal toxicity (Table 5-1)
From page 170...
... In the case of the postmarketing situation that currently exists for dietary supplements where limited resources may necessitate a focus primarily on serious adverse effects, it is appropriate to apply some of the scientifically accepted concepts to determine which serious adverse effects observed in animals warrant further investigation or suggest an unreasonable risk may exist. In developing safe limits, uncertainty factors have been applied to animal toxicity threshold values (NOAELs)
From page 171...
... Situations described in the righthand column of Table 5-2 signal the highest degree of concern for human risks and suggest a significant risk to human health, even in the absence of any human information regarding adverse effects. Situations described in the middle column are of less concern, and ingredients with this level of evidence may not represent a significant health risk unless such risk is confirmed with human or other types of data.
From page 172...
... · Much of the animal study data available for dietary supplement ingredients will not have the characteristics of ideal studies, but these studies should nonetheless be considered if they suggest possible human health risk. · Animal studies that predict possible serious harm or death warrant more attention than those that predict mild, self-limiting effects in humans.
From page 173...
... 2001. Guidance for Industry: S7A Safety Pharmacology Studies for Human Pharmaceuticals.
From page 174...
... Brisbane: Queensland Poisonous Plants Committee. Tomatis L


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