The information in Chapters 4 through 8, which describe the scientific bases for evaluating safety of dietary supplement ingredients, is critical in determining which dietary supplement ingredients warrant the most immediate attention, that is, in setting risk-based priorities. However, it is also appropriate to take other information into consideration when setting priorities. For example, given similar degrees of concern about risk, attention from the Food and Drug Administration (FDA) is more appropriately directed towards a supplement that is being used by a greater portion of the population. It is also important to consider the safety of the most sensitive groups. This chapter describes these additional considerations.
GUIDING PRINCIPLE: When data indicate that an identifiable subpopulation may be especially sensitive to adverse effects from a specific dietary supplement ingredient, this should be taken into account when setting priorities.
When considering the safety of dietary supplement ingredients, it is important to consider that some individuals may be particularly vulnerable to adverse effects from certain dietary supplement ingredients. Vulnerable subpopulations can be defined as groups of individuals who are more likely to experience an adverse event related to the use of a particular dietary
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Dietary Supplements: A Framework for Evaluating Safety 9 Vulnerable Groups and Prevalence of Use The information in Chapters 4 through 8, which describe the scientific bases for evaluating safety of dietary supplement ingredients, is critical in determining which dietary supplement ingredients warrant the most immediate attention, that is, in setting risk-based priorities. However, it is also appropriate to take other information into consideration when setting priorities. For example, given similar degrees of concern about risk, attention from the Food and Drug Administration (FDA) is more appropriately directed towards a supplement that is being used by a greater portion of the population. It is also important to consider the safety of the most sensitive groups. This chapter describes these additional considerations. USE BY VULNERABLE SUBPOPULATIONS GUIDING PRINCIPLE: When data indicate that an identifiable subpopulation may be especially sensitive to adverse effects from a specific dietary supplement ingredient, this should be taken into account when setting priorities. When considering the safety of dietary supplement ingredients, it is important to consider that some individuals may be particularly vulnerable to adverse effects from certain dietary supplement ingredients. Vulnerable subpopulations can be defined as groups of individuals who are more likely to experience an adverse event related to the use of a particular dietary
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Dietary Supplements: A Framework for Evaluating Safety supplement ingredient, or individuals in whom the specific adverse effects identified are more likely to be serious in comparison with the general population. Characteristics that contribute to such vulnerability may be physiological (including genetic predisposition), disease-related, or due to other aspects, such as lifestyle or therapeutic interventions that are commonly utilized by a subgroup. Age-Related Changes Physiological characteristics frequently result in an individual’s increased susceptibility compared with the general population; an example of this is the change in the capacity to metabolize various dietary supplement ingredients across the lifespan. Changes in metabolism may lead to variable concentrations of active compounds at sites of action, resulting in different responses. For example, elderly individuals are a potential vulnerable subpopulation for some ingredients in that aging is associated with changes in the ability to digest, metabolize, or excrete some ingested substances (Munro, 1989; Rosenberg et al., 1989). Other age-related changes may involve receptors or kinetic parameters, such as the volume of distribution (Mangoni and Jackson, 2004). Supplement ingredients that are normally excreted or altered by the kidney or liver may potentially pose a greater risk to the elderly subgroup than to a younger population. This fact should be considered for supplements specifically directed toward an older population, such as those consumed to prevent osteoporosis or Alzheimer’s disease. Children also metabolize some chemical substances differently than do adults, which for certain supplement ingredients may make children more susceptible to adverse effects (Guzelian et al., 1992). This should be taken into consideration for supplements marketed toward children or likely to be given to children. Infants have limited liver function that may make them particularly susceptible to certain hepatotoxic substances (Brown, 1968). Pregnancy and Fetus Considerations Pregnancy-related physiological changes may make pregnant women more susceptible to adverse effects associated with particular dietary supplement ingredients. In addition, the fetus may also be particularly vulnerable; special concerns are warranted for supplement ingredients that may have teratogenic effects. Fetuses may be harmed if they are exposed to dangerous substances in utero, as may infants if they are exposed to substances released into human milk. A well-known example is the teratogenicity of high doses of vitamin A in the periconceptual period (Eckhoff and Nau, 1990; Lammer et al., 1985; Rothman et al., 1995). Animal studies or chemical
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Dietary Supplements: A Framework for Evaluating Safety characteristics may provide clues that fetuses or infants are particularly susceptible to other supplement ingredients as well. Given these concerns, unless a supplement has been specifically tested for risk during pregnancy or is required for medical reasons, use of dietary supplements during pregnancy cannot be supported. Disease Considerations In addition to life stages that may alter responses to ingested substances, the presence of disease may also result in enhanced susceptibility to adverse effects from particular ingredients. Disease or pre-existing conditions, such as hypertension, cardiac arrhythmias, or other early stages of cardiovascular disease, can be expected to exacerbate susceptibility to substances that specifically affect the organ exhibiting the disease or condition. In conditions such as hepatitis or renal disease, xenobiotic clearance and excretion is markedly altered, allowing compounds that are normally cleared rapidly to accumulate to toxic levels. Similarly, dietary supplement ingredients that affect insulin and glucose regulation are of concern to individuals with diabetes, unless data are available that mitigate this concern. Interactions with Other Xenobiotics People who use prescribed medications on a chronic basis, many of which are critically important to their health, may also be at greater risk of harm from interactions of their drugs with various supplement ingredients. For example, people who have HIV/AIDS or other chronic diseases may be taking drug combinations that can interact with supplement ingredients, such as St. John’s wort, that alter cytochrome P450 activity (Ernst, 1999; Piscitelli et al., 2000). (See Chapter 8 for a more detailed discussion on interactions.) Interactions between drugs and dietary supplements may be of particular concern when both are taken for the same pathology and are thus potentially taken at the same time, and possibly without the knowledge of the prescribing physician. For example, vitamin E supplements, which are often recommended to patients with atherosclerotic vascular disease, may interact with statin drugs (Brown et al., 2001). Summary of Vulnerable Population Considerations Certain segments of the population may be particularly susceptible to the effects of some dietary supplement ingredients for a variety of reasons. Factors such as age, disease, pre-existing conditions, ethnicity, sex, or history of specific xenobiotic exposure (such as to drugs or other chemicals,
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Dietary Supplements: A Framework for Evaluating Safety including pesticides) can alter the effects of supplement exposure, and supplement exposure can affect pharmacodynamics and clearance of drugs prescribed for health reasons. When evaluating risk and reviewing data, it is important to ask if ingredients are more likely to cause harmful effects to particular subgroups of the population. In this Framework, vulnerability of a population subgroup is described as a modifying factor in that whether identifiable subpopulations are particularly susceptible to harm should always be taken into consideration when setting priorities. In conclusion, greater priority should be given to dietary supplement ingredients for which there is a concern about risk to particular subpopulations, especially if those subpopulations are known to consume the particular ingredient of concern. PREVALENCE OF USE IN THE POPULATION GUIDING PRINCIPLE: Ingredients that are widely used by the general population should be given higher priority for critical safety evaluation than less widely used ingredients with similar degrees of safety concerns. This is consistent with the public health goal of producing the most impact from limited resources. The relative number of individuals who could be at risk for harm due to overall use of a particular dietary supplement ingredient in the United States can be roughly estimated from various sources that provide estimates of the relative popularity of different ingredients. Across the wide variety of dietary supplement ingredients that are currently available, there is a wide range of usage patterns in the population. Some ingredients are used only rarely or by a small fraction of the population, while others are used by a considerable fraction, and/or taken frequently and chronically by a subset of the population, such as the elderly or athletes. Dietary supplements that are used only rarely, or are used by few consumers, would be expected to result in a low level of exposure on a population basis. Estimating prevalence of use allows a qualitative consideration of population exposure and therefore the relative number of individuals that may be at risk if an ingredient is harmful—a factor that is important in setting priorities to optimize the impact of a risk/safety evaluation on public health. That is, from a public health perspective, it is more logical to first allocate resources to evaluate potentially harmful ingredients may harm many people before evaluating those ingredients that may only affect a small fraction of the population, assuming other information about risk is equivalent. Relative consumption and prevalence of use of various dietary supple-
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Dietary Supplements: A Framework for Evaluating Safety ment ingredients in the general population can be estimated from two types of data. One type is industry estimates of production or sales. Dietary supplement industry publications, such as the Nutrition Business Journal, provide such data. Additionally, manufacturers and distributors collect production data, unit sales data, and total sales information in dollars as a normal component of business operations. The industry may be willing to make this information available. The second type of data about prevalence of use is that collected in surveys about supplement usage. Such surveys ask respondents about patterns of use and can provide data on prevalence of use in the general population as well as in specific population subgroups. National surveys that have traditionally collected information from a large number of persons regarding health issues and conventional food consumption information are increasingly also collecting valuable information about specific supplement use. An example is the expanded monitoring efforts of the National Health and Nutrition Examination Survey (CDC, 2004). Although it may be 2 to 3 years before the collected information is available, the planned expanded data collection will provide more detailed and useful information than is currently available in the older national survey data sets. There are inherent limitations to many of the older survey data sets. They are often deficient in reporting frequency of use information and brand-specific information on ingredients and concentration, and they contain limited information on the collection and interpretation of data on products or ingredients that are typically used in combination (in addition to formulation and sales of single-ingredient products). In summary, when setting priorities for which dietary supplements warrant attention first, it is not only appropriate to consider use by subpopulations that may be at risk for adverse effects, but also the extent of use by the general population, assuming that other information about risk is equivalent or comparable. Ingredients that are widely used by the general population should be given higher priority for critical safety evaluation than less widely used ingredients with similar degrees of safety concerns. These concepts are consistent with the FDA’s mission of protecting the public health. REFERENCES Brown AK. 1968. Bilirubin metabolism in the developing liver. In: Assali N, ed. Biology of Gestation. Vol 2. New York: Academic Press. Brown BG, Zhao XQ, Chait A, Fisher LD, Cheung MC, Morse JS, Dowdy AA, Marino EK, Bolson EL, Alaupovic P, Frohlich J, Albers JJ. 2001. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med 345: 1583–1592.
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