5
Framework to Review the Safety of Dietary Supplements for Use by Military Personnel

BACKGROUND

The increasing popularity of dietary supplements among civilians and military personnel has raised questions about their safety and efficacy for both populations. In the United States, various government agencies are charged with ensuring the safety of consumable products by developing and implementing policy according to their legal authority. In the United States, decisions regarding the safety of ingested substances are made using three models, based on the nature and intended use of each substance. The basic models are the food model (based on the assumption, derived from historic consumption, that all foods are safe and therefore, no premarket safety assessment is necessary), the food additive model (based on premarket safety assessments submitted to the U.S. Food and Drug Administration [FDA] by manufacturers), and the drug model (based on risk-benefit assessments submitted to the FDA by manufacturers).

The Dietary Supplement Health and Education Act (DSHEA) of 1994 designated the FDA as the agency responsible for determining whether a marketed dietary supplement is unsafe (Dietary Supplement Health and Education Act of 1994, Public Law 103-417, 108 Stat 4325, 103rd Congress, October 25, 1994). The unique nature of dietary supplements (i.e., they are legally categorized as foods but are used to enhance health) and their history of use (i.e., some have been used as medicines for centuries by other cultures) have resulted in difficulty and confusion in establishing and implementing policies to address their safety. Despite wide concurrence that, given the nature of these products, a premarket approval pro-



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5 Framework to Review the Safety of Dietary Supplements for Use by Military Personnel BACKGROUND The increasing popularity of dietary supplements among civilians and military personnel has raised questions about their safety and efficacy for both populations. In the United States, various government agencies are charged with ensuring the safety of consumable products by developing and implementing policy according to their legal authority. In the United States, decisions regarding the safety of ingested substances are made using three models, based on the nature and intended use of each substance. The basic models are the food model (based on the assumption, derived from historic consumption, that all foods are safe and therefore, no premarket safety as- sessment is necessary), the food additive model (based on premarket safety assessments submitted to the U.S. Food and Drug Administration [FDA] by manufacturers), and the drug model (based on risk-benefit assessments submitted to the FDA by manufacturers). The Dietary Supplement Health and Education Act (DSHEA) of 1994 designated the FDA as the agency responsible for determining whether a marketed dietary supplement is unsafe (Dietary Supplement Health and Education Act of , Public Law 103-417, 108 Stat 4325, 103rd Con- gress, October 25, 1994). The unique nature of dietary supplements (i.e., they are legally categorized as foods but are used to enhance health) and their history of use (i.e., some have been used as medicines for centuries by other cultures) have resulted in difficulty and confusion in establishing and implementing policies to address their safety. Despite wide concur- rence that, given the nature of these products, a premarket approval pro- 

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 FRAMEWORK TO REVIEW THE SAFETY cess would be appropriate to address their safety, there is no such process in place. While DSHEA mandates that manufacturers wishing to market new dietary supplement ingredients inform the FDA of their intention, this notification is often not accompanied by a safety profile of the product. The FDA relies on a postmarket adverse event surveillance system to monitor adverse effects and, along with other supporting scientific data, to take action against any dietary supplement identified as unsafe after it has been marketed. However, the voluntary nature of reports by consumers or others to the FDA presents important limitations, such as low reporting rate or poor data quality (see Chapter 6). The 2007 Dietary Supplement and Nonprescription Drug Consumer Protection Act represents a step for- ward in ensuring safety by mandating that companies report to the FDA any serious adverse event derived from the use of dietary supplements, but the success of this act in establishing an effective signaling system to identify supplement ingredients particularly in need of safety evaluation is still unknown. The act defines the term serious aderse eent as an adverse event that (A) results in (i) death; (ii) a life-threatening experience; (iii) inpatient hospitalization; (iv) a persistent or significant disability or incapacity; (v) a congenital anomaly or birth defect; or (B) requires, based on reasonable medical judgment, a medical or surgical intervention to prevent a previ- ously listed outcome described under subparagraph (A). Also, in 2007, the FDA published the final rule, stipulated under DSHEA, establishing the minimum current good manufacturing practices (cGMPs) required for activities related to manufacturing, packaging, la- beling, and storing dietary supplements to ensure their quality. This rule ensures consistency in product composition, but not the safety or efficacy of that product. The FDA is empowered to initiate regulatory action (e.g., banning a dietary supplement, taking an enforcement action [e.g., seizure or injunction] against a product or firm, or alerting the public) when the agency has evidence a product violates a provision of the Federal Food, Drug, and Cosmetic Act (FFD&C Act). Evidence that a product may be unsafe could include postmarket reports of severe adverse events, reports in the scientific literature of harm associated with exposure to a particular product or ingredient, or evidence of the presence of an adulterant such as an unforeseen contaminant or a purposeful adulterant. In light of the growing use of dietary supplements, the FDA requested in 2002 that the Institute of Medicine (IOM) provide a process or frame- work for evaluating the safety of dietary supplement ingredients. Highlights of the IOM report Dietary Supplements: A Framework for Ealuating Safety (2005) were presented at the February 2007 workshop (see Jeffery in Appendix B).

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 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL The 2005 IOM report recognizes that the potential for a significant or unreasonable risk resulting from consumption of a dietary supplement var- ies depending on the specific circumstances of its use (e.g., under tempera- ture extremes) or for specific populations (e.g., military personnel; see also Chapter 9 of the 2005 IOM report for a discussion of vulnerable groups). Thus, a vulnerable group may be at far greater risk from adverse effects of a given supplement than the general public. An example would be persons operating motor vehicles, who should not take sedative supplements such as valerian. Because neither federal dietary supplement policies nor the safety framework outlined in the 2005 IOM report was created with the specific needs (e.g., unique policies, behaviors, environmental stresses, and performance requirements) of the military population in mind, the U.S. Department of Defense (DoD) requested that this committee assess the applicability of the 2005 IOM report framework to a military setting and establish how it could be modified to determine which supplements need active management by the military. The committee concluded that the 2005 IOM report’s framework for the general population is not directly applicable to military personnel for reasons that include the military’s need for optimal health and performance as well as the high demands for readiness and success in military operations. Benefits and/or risks to military personnel from use of a particular dietary supplement might also differ from those of the general population owing to specific unit missions and environments; for example, the thermoregulatory effects of some dietary supplements could be critical for military person- nel operating in extreme temperatures, while they would be less important for the general population or for military personnel deployed to a more temperate area. Some groups of military personnel might experience risks and benefits from the use of dietary supplements different from those of other military personnel because of their unique responsibilities and tasks (e.g., aviators, those with access to nuclear weapons, or those conducting special operations). The U.S. regulatory model to manage the use of dietary supplements may also be inadequate for certain military populations (see Chapter 1, Box 1-3). For example, because of the potentially life-threatening consequences of being in suboptimal mental or physical health while conducting military operations, military leadership might need to develop an active monitoring system, rather than basing decisions only on the passive system of volun- tarily reported adverse events now in use (see Chapter 6). Furthermore, the potential gains in health or performance from the use of some dietary supplements need to be considered in managing their use. For instance, if dietary supplement X causes slight dehydration but substantially improves alertness, the management of X by military leadership might be different

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 FRAMEWORK TO REVIEW THE SAFETY from that of dietary supplement Y, which induces a similar level of dehydra- tion but imparts little benefit. To summarize, this IOM committee was asked to review the 2005 IOM report’s framework for evaluating the safety of dietary supplements and assess whether modifications are necessary for its application to the military. This chapter does not enumerate the specific series of in vitro and in vivo toxicological and clinical tests that would be required to evaluate the safety of a dietary ingredient; these will vary with the specific ingredient(s), the users, and other factors. Instead, the chapter includes a framework to review the available scientific evidence and determine the level of concern; this is to be used as a tool to help military decision makers establish poli- cies on the use of dietary supplements. In contrast to the 2005 IOM report framework, which—in accordance with the FDA’s mandate—focused only on safety, this committee has provided general guidance for the military on integrating considerations of efficacy and safety when making policy on dietary supplement use. The development of a framework to perform a complete risk-benefit analysis is beyond the scope of this report. It is also beyond the scope of this report to recommend definitive management actions. Examples are provided of possible actions (e.g., restricting or recommending the use of specific dietary supplements, developing educational programs) based on the level of concern (and the potential for benefit). To demonstrate applica- tion of the framework recommended, the committee reviewed a number of dietary supplements on the basis of published safety and efficacy reports (see Chapters 3 and 4) and identified those that might pose concerns or be of benefit. In addition, the committee’s overall approach (i.e., including application of the framework and recommendations for action) was ap- plied to a subset of those dietary supplements (Appendix D); it was outside the committee’s task to provide a review of all dietary supplements. These monographs and case studies should be considered as examples; as recom- mended below, determining the specific actions to take in response to a di- etary supplement review should be the prerogative of military leadership. SAFETY FRAMEWORK FOR DIETARY SUPPLEMENTS: MODIFICATIONS FOR MILITARY USE The committee’s recommended approach to manage the use of dietary supplements in a military context comprises four related components: (1) improving monitoring of the use of dietary supplements by military per- sonnel, (2) using a framework to determine the level of concern for dietary supplements in a military context, (3) implementing a system to report

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00 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL adverse events associated with dietary supplements, and (4) expanding education on dietary supplements. This section describes the second component, that is, elements of the safety framework outlined in the 2005 IOM report that are particularly use- ful to the military in its need to understand the safety (and possible benefits) of the use of dietary supplements by military personnel. (For greater detail on the regulatory background and the statement of task of the 2005 IOM Committee on the Framework for Evaluating the Safety of Dietary Supple- ments, see Jeffery in Appendix B.) The 2005 IOM report framework consists of a process for prioritizing, evaluating, and describing available information to establish risk of harm, together with a second, supportive component: a set of science-based princi- ples that serve as guidelines for evaluating risk to human health (see Jeffery, Figure B-24, in Appendix B). It characterizes the nature of the scientific evidence that is likely to be available to the FDA and describes a process for organizing this evidence to assess the level of concern for a dietary supple- ment ingredient. A “significant or unreasonable risk of illness or injury” is the standard that warrants regulation by the FDA under the FFD&C Act, as amended by DSHEA. The process outlined in the 2005 IOM report is divided into three steps: signal detection, initial signal review to determine a preliminary level of concern, and integrated safety evaluation of dietary supplements. This process provides a basis for determining whether a di- etary supplement is unsafe and for translating a serious concern into safety management actions. For example, a high level of initial concern based on a signal that leads to a high potential for a “significant or unreasonable risk of illness or injury” warrants a full evaluation of safety. Proving that a dietary supplement presents an unreasonable risk is a substantial undertaking requiring valuable time and resources. The FDA, which bears responsibility for the safety of all dietary supplements on the market, is presently limited to responding to reports of serious adverse events as the primary signal for action. The DoD could take a more proac- tive stance, choosing to evaluate the effects of a dietary supplement and take management actions based on criteria pertinent to the demands of military service. Thus, the military may choose to focus attention on determining the safety of those dietary supplements with the highest volume of sales, even if there have been no adverse events reported for the general population. Furthermore, the scientific basis for concern may be more stringent and may include evidence of more subtle effects than those causing concern for the general public. For these reasons, the 2005 IOM report framework has been adapted to meet the specific needs of the military. Described below are the three steps (i.e., signal detection, initial review of signals, and integrated safety evaluation) described in the 2005 IOM report, followed by their adaptation for the military.

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0 FRAMEWORK TO REVIEW THE SAFETY Signal Detection The 00 IOM Safety Framework for Dietary Supplements: Aderse Eent Monitoring The 2005 IOM report suggested that, given the limited resources avail- able to the FDA, a supplement should undergo a safety review only when the signal of a serious adverse event indicates the need. However, should resources permit, it was proposed that the FDA’s attention should focus on signals that indicate a serious health problem may result from ingestion of a dietary supplement ingredient. The 2005 IOM report framework suggested that if the FDA were able to operate proactively, review of a dietary supplement ingredient should be initiated on the basis of either a high prevalence of use in the general popu- lation, or a high level of use by a particularly vulnerable population. As Modified for the Military: Aderse Eents and Frequency of Use Monitoring The military should proactively concern itself not only with dietary supplements associated with an adverse event but also with those most commonly sold on base, and with consideration for the safety of those military personnel who, because of their duties, would be particularly vul- nerable to the adverse effects of specific supplements. For example, pilots might be susceptible to effects including hypoxia, cognitive decrements, or loss of spatial orientation. Similarly, those on active duty in adverse environments might be particularly vulnerable to supplements causing loss of thermal regulation (see Chapter 1, Box 1-3 for a list of special military populations). Conversely, if there were supplements that could aid in pre- vention of these adverse effects, this information might be of considerable benefit to the military. Initial Review of Signals The 00 IOM Safety Framework for Dietary Supplements: Seerity of Aderse Eents The second step in the process outlined in the 2005 IOM framework is the initial review of available information on the signal (i.e., adverse event reports). First, the nature of the signal information is examined to determine the preliminary level (low, moderate, or high) of concern about a potential risk to human health. This is not a detailed analysis of data, but rather an assessment to determine whether further evaluation of the

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0 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL supplement is indicated. If review of the reports shows an isolated case lacking reliable evidence that the supplement was likely to be a cause, the resulting low level of concern would indicate no further need for action at that time. If signal review results in even a moderate level of concern traced directly to the supplement, then other criteria, such as prevalence of use or potential to adversely affect vulnerable subpopulations, should be considered, which might result in elevation of the signal concern level to high. Signal review would typically be triggered by an adverse event report of medium or high concern. As Modified for the Military: Seerity of Aderse Eents and Frequency of Use Recommendation 4: The decision to initiate a review of a dietary supplement should be based on two criteria: severity and number of adverse events, and prevalence of use. The selection of dietary supple- ments for review should consider the particular vulnerabilities of the military subpopulations, which would depend on their missions and mission environments. Severity and number of adverse events As with the general population, one set of criteria relies on adverse event(s) reported by military or nonmili- tary personnel. (See Chapter 6 for recommendations on a system to monitor adverse events for the military.) Military health care professionals should identify any adverse events associated with dietary supplement use that might compromise the perfor- mance or survivability of military personnel. Such adverse events would include those that affect vigilance; have a significant adverse impact on alertness, mood, or cognitive performance; cause hypoxia; or affect bal- ance or spatial orientation. They would also include impairment of clot- ting, hydration, immune function, or thermoregulation. Conditions to help categorize adverse events as high, moderate, low, and minimal are listed in Box 5-1. Summaries of adverse event reports should be submitted to the military committee or entity designated to oversee dietary supplements (herein referred to as the designated oversight committee; see Chapter 6), who will identify a signal of concern for a dietary supplement and deter- mine whether a review is appropriate. When the adverse event reported is serious or might compromise per- formance or survivability, the committee proposes a two-part response. The first step is to determine whether urgent action (e.g., new policies; see Figure 5-1) is warranted. Second, in conjunction with policy implemention and enforcement, a safety and efficacy review should be conducted. Adverse events of moderate concern might not signal the need for new policy, al-

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0 FRAMEWORK TO REVIEW THE SAFETY though the military should initiate a safety review (Figure 5-1). If no adverse effects are being noted from the use of a specific supplement and its safety review reveals no concern, then the determination would be made that the dietary supplement is of minimal concern and no further evaluation would be needed. Nevertheless, due to low reporting rates of adverse events,1 the lack of such reports does not necessarily mean that the dietary supplement is safe. Further, the committee believes that because these products are bio- active, high frequency of use calls for a review of safety, unless the dietary supplement has already been declared to be of minimal concern. The committee cautions that the linking of an adverse event to a dietary supplement ingredient might be confounded if the product contains mul- tiple ingredients, or adulterants or adventitious contaminants. In the case of multiple ingredients, determination of causation for a particular substance requires careful review of all the individual ingredients in a product or the combination product itself. If contamination is the issue, then attribution of the source of the event is even more challenging. In either case, and until the cause of the adverse event is determined, the military might need to apply policies for the use of the suspect product as well as for any other product containing any of the ingredients found in the suspect product. Prevalence of use A second criterion to commence a review relies on a proactive initiative by military leadership in response to the use of a new supplement similar to a drug or supplement that has previously caused safety concerns (e.g., bitter orange contains synephrine, closely related to ephedrine, the active component in ephedra); the high frequency of use of a supplement; or an increase in frequency of use in the general military population or specific subpopulations. To make such decisions, data from dietary supplement sales and survey data on dietary supplement use within the military would be required (see Chapter 2). For example, the military should review data on sales of dietary supplements from outlets located on base (e.g., Army and Air Force Exchange Service/Navy Exchange Service [AAFES/NEX], fitness centers) annually to determine which supplements have become popular. Because of the low reporting rates for adverse events, the lack of data on adverse events does not necessarily show that a dietary supplement is safe. Also, because these products are bioactive, a review of the safety of widely used dietary supplements is warranted unless the dietary supplement has been declared to be of minimal concern. If no ad- 1 The2007 Dietary Supplement and Nonprescription Drug Consumer Protection Act defines the term “serious adverse event” as an adverse event that (A) results in (i) death; (ii) a life- threatening experience; (iii) inpatient hospitalization; (iv) a persistent or significant disability or incapacity; (v) a congenital anomaly or birth defect; or (B) requires, based on reasonable medical judgment, a medical or surgical intervention to prevent a previously listed outcome described under subparagraph (A).

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0 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL BOX 5-1 Description of Concern Levels Specific to Use of Dietary Supplements by Military Personnel High concern • Human epidemiological studies or adverse effects signaling: Product has been found responsible for a serious adverse event Performance degradation (e.g., for those deployed, in training, or in combat settings): – Product significantly affects vigilance – Product has significant adverse impact on alertness/drowsiness, mood alteration, cognitive performance – Product significantly induces hypoxia – Product significantly affects balance and spatial orientation A decrease in survivability (e.g., for those deployed, in training, or in combat settings): – Product significantly inhibits clotting time – Product significantly promotes dehydration – Product significantly inhibits immune system – Product significantly disrupts body’s ability to maintain thermal regulation • Animal data signaling: Serious adverse events as described above for human data, seen in ani- mals at doses 10× recommended exposure for humans Neoplasia Severe organ toxicity (necrosis/dysplasia) Reproductive failure/developmental effects Severe neurological/behavioral changes • In vitro data signaling: Multiple different assays suggest the same pathological condition related to serious adverse events described for human data above Concentrations of the dietary supplement causing severe adverse effects in vitro are similar to reported blood or plasma levels in humans following consumption of this dietary supplement Chemical or plant species is similar to known toxic compound and/or banned dietary supplement, or similar to products having adverse effects described above in humans verse effects are noted from the use of a specific supplement and its safety review reveals no concern, then the determination would be made that the dietary supplement is of minimal concern and no further evaluation would be needed. Many factors need to be taken into consideration in determining a level of concern from adverse events reported, including the strength of the

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0 FRAMEWORK TO REVIEW THE SAFETY Moderate Concern • Human epidemiological studies or adverse events signaling: Performance degradation (e.g., for those deployed, in training, or in combat): – Product has moderate impact on hydration, gastrointestinal function (e.g., diarrhea, nausea), thermal regulation, alertness/drowsiness, mood, or cognitive performance or may induce shortness of breath or syncope A decrease in survivability (e.g., for those deployed, in training, or in combat): – Product has moderate impact on clotting time – Product has moderate or low ability to inhibit immune system • Animal data signaling: Moderate organ toxicity (atrophy, hyperplasia) Reduced reproductive capacity/mild developmental effects Altered clinical chemistry outside the reference range Those adverse effects listed above as serious in humans, occurring at 100× the recommended dose range Low Concern • Human epidemiological studies or adverse events signaling: Performance degradation: – Product has low impact on hydration, gastrointestinal function (e.g., diarrhea, distress, nausea), alertness/drowsiness, thermal regulation, mood, or cognitive performance No decrease in survivability (product has no known impact on immune response or bleeding/clotting time) • Animal data signaling: Reduced food intake Enzyme changes Reversible degenerative changes Minimal Concern • Human epidemiological studies or adverse events signaling: No serious adverse events No performance degradation (product has no known impact on hydration, gastrointestinal function, thermal regulation, alertness/drowsiness, mood, or cognitive performance) No decrease in survivability (product has no known impact on immune response or bleeding/clotting time) evidence (e.g., how many adverse events were associated with the dietary supplements, the strength of the association, level of intake, intake of other medications or supplements, actual circumstances of use, characteristics of the individual user). The committee recommended that the evidence be reviewed and that the level of concern be determined by taking into consideration not only the the strength of the evidence but also the tasks

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Signal Detection-Adverse Effects Proactive Initiative 0 Severe Adverse Effects Adverse Effects, Not Severe Safety Review B. Review of Original Research A. Review of Safety Using C. Review of Interactions Pertaining to Specific Military Reviews or Original Research if with Medications Concernsa Reviews Are Nonexistent Integrate Data from A, B, C and Decide on Level of Concern (See Box 5-1) High Concern Moderate Concern Low Concern Minimal Concern FIGURE 5-1 Framework to review the safety of dietary supplements. aHigh physical activity, calorie restriction, hydration, gastrointestinal tract (diarrhea/nausea), liver health/function (xenobiotic clearance), cardiovascular health, mood/behavior altering, alertness/drowsiness, extreme heat/cold, injury/bleeding. Figures S-1 and 5-1, R01214

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 FRAMEWORK TO REVIEW THE SAFETY Interactions with Medicationsf or Other Withdrawal Concern Putative Benefitsg Levelh Bioactive Substances Effects Moderate Sedative hypnotics and No data Some evidence of anesthetics: Theoretical found improvement of sleep synergy Substantial evidence of circadian reentrainment under controlled conditions Moderate potential for benefit (evidence of circadian benefits and some sleep benefits) Moderate Sedative hypnotics and No data Inconclusive evidence that anesthetics: Theoretical found valerian improves sleep synergy Low potential for benefit (evidence of minimal beneficial effects) Minimal Unknown but unlikely, No data Evidence of improved depending on individual found exercise performance ingredients Supplement essential nutrients High potential for benefit (substantial evidence of benefits and high desirability) continued

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 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL TABLE 5-3 Continued Potential Detrimental Effects to Dietary Military Supplementsb Performancec Military Survivabilityd Other Health Riskse Sports drinks No data Hyponatremia (with Could contribute found excessive use) unnecessary calories for inactive personnel Vitamins and Minerals Calcium No data Minimal when below Minimal when below UL found Tolerable Upper Intake Level (UL)

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 FRAMEWORK TO REVIEW THE SAFETY Interactions with Medicationsf or Other Withdrawal Concern Putative Benefitsg Levelh Bioactive Substances Effects Minimal Unknown but unlikely, No data Evidence of improved depending on individual found exercise performance ingredients Some evidence of increased muscle protein synthesis, superior hydration, and reduction in muscle damage after strenuous exercise when drinks contain protein; requires further substantiation Plasma level better maintained during sweating when electrolytes are provided High potential for benefit (substantial evidence of benefits and high desirability) Minimal when May reduce absorption and/ No data To reach adequate levels by or efficacy of some found supplementing the diet below UL medications Sustain bone health and mood states; potential for further benefits with supplemental amounts High potential for benefit (substantial evidence of benefits and high desirability) continued

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 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL TABLE 5-3 Continued Potential Detrimental Effects to Dietary Military Supplementsb Performancec Military Survivabilityd Other Health Riskse Iron No data Minimal when below UL Minimal when below UL found Selenium No data Minimal when below UL Minimal when below UL found Zinc No data Minimal when below UL Minimal when below UL found Multivitamins/ No data Minimal when below UL Minimal when below UL multiminerals found

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 FRAMEWORK TO REVIEW THE SAFETY Interactions with Medicationsf or Other Withdrawal Concern Putative Benefitsg Levelh Bioactive Substances Effects Minimal when No data To reach adequate levels by found supplementing the diet below UL Sustain physical and cognitive performance High potential for benefits (substantial evidence of benefits and high desirability) Minimal when No data To reach adequate levels by found supplementing the diet below UL Maintain immune function; potential for further benefits with supplemental amounts High potential for benefits (substantial evidence of benefits and high desirability) Minimal when No data To reach adequate levels by found supplementing the diet below UL High potential for benefit (substantial evidence of benefits and high desirability) Minimal when No data To reach adequate levels by found supplementing the diet below UL High potential for benefit (substantial evidence of benefits and high desirability) continued

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0 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL TABLE 5-3 Continued Potential Detrimental Effects to Dietary Military Supplementsb Performancec Military Survivabilityd Other Health Riskse Vitamin C No data Minimal when below UL Minimal when below UL found Vitamin D No data Minimal when below UL Minimal when below UL found Vitamin E No data Minimal when below UL Minimal when below UL found aThe monographs used to produce this table were developed in order to evaluate the review process outlined in Chapter 5. The monographs present scientific reviews of safety and efficacy, but do not attempt to provide a final assessment of safety or efficacy. bComposition of dietary supplements varies widely; these are general categories and many include other ingredients or a combination of ingredients. cCausing detriments to performance during military tasks (e.g., physical endurance, muscle strength, alertness, memory, stress, sleep patterns). dCausing detriments to military survivability (e.g., bleeding or injury, dehydration, malfunc- tion of gastrointestinal tract, stress, or altered behavior). eCausing risks to health, excluding those in note 2 above. fRefers to the 100 medications most prescribed for military personnel. gImprovements of performance during military tasks (e.g., physical endurance, muscle strength, alertness, memory, stress relief, sleep patterns) based on level of desirability of the benefit to the military and level of science documenting a benefit (see details in Table 5-2). hHigh, moderate, low, or minimal as described in Box 5-1 and modified based on putative benefits.

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 FRAMEWORK TO REVIEW THE SAFETY Interactions with Medicationsf or Other Withdrawal Concern Putative Benefitsg Levelh Bioactive Substances Effects Minimal when No data To reach adequate levels by found supplementing the diet below UL Maintain immune function High potential for benefit (substantial evidence of benefits and high desirability) Minimal when No data To reach adequate levels by found supplementing the diet below UL Maintain bone health High potential for benefits (substantial evidence of benefits and high desirability) Minimal when Aspirin: Antithrombotic Unknown To reach adequate levels by effects but unlikely supplementing the diet below UL Warfarin Maintain immune function High potential for benefit (substantial evidence of benefits and high desirability) i“No data found” means that there were no data found in the subject area showing an effect, either because the studies reviewed did not investigate this subject area or because, when in- vestigated, there was no effect (i.e., health risk). Absence of evidence of risk, a frequent reality, does not necessarily indicate that there is no risk. Even if a study reported a lack of adverse effects, if the study is not adequately designed to identify risk (e.g., it is insufficiently pow- ered, incompletely reported, does not include positive controls, or otherwise has inadequate mechanisms for detecting adverse events), its scientific validity is reduced or even null. jImmune function enhancers, antioxidants, energy supplements, enhance recovery or performance. kRefers to supplements containing macronutrients for energy or essential nutrients below the UL to meet physiological needs level, or electrolytes to replenish those lost during exercise. If energy supplements contain other ingredients (e.g., creatine), then an evaluation of each individual ingredient and interaction is warranted.

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 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL military unit trainers, and health care providers to inform service members. The committee cautions that such a summary table could be misinterpreted and therefore is not to be used as a sole source of information; it is meant to be used by those with sufficient scientific expertise as a tool to develop educational materials. Communication with service members should not establish a presumption that using dietary supplements is the norm or the expected behavior. CHALLENGES OF THE PROPOSED FRAMEWORK FOR MILITARY PERSONNEL The three types of challenges in evaluating the safety or efficacy of dietary supplements with the framework proposed by this committee are outlined in this section. Insufficient Scientific Data The practical value of the proposed framework depends on publicly available data. One critical challenge is acquisition of sufficient scientific data from literature searches to support an informed decision about the safety and efficacy of a dietary supplement within the military. Although there is an abundance of data for a few supplements, such as ephedra, the dearth of data for others hinders the determination of any definitive con- clusion and further decision making. In Chapter 7, the committee provides its recommendations on the military undertaking research to address data gaps in areas of significant concern. The committee emphasizes that absence of evidence of risk, a frequent reality, does not necessarily indicate that there is no risk. Even if a study reported a lack of adverse effects, if the study is not adequately designed to identify risk (e.g., it is insufficiently powered, incompletely reported, does not include positive controls, or otherwise has inadequate mechanisms for detecting adverse events), its scientific validity is reduced or even null. Multi-Ingredient Dietary Supplements Dietary supplements commonly contain multiple ingredients, and their compositions are frequently altered (e.g., they are reformulated with dif- ferent proportions, amounts, and even ingredients) without any product name change. Finding data on the safety (or efficacy) of the myriad multi- ingredient products in the market is yet a bigger challenge than finding data on single-ingredient products. The committee concluded that these products merit special attention by frequent monitoring of their use, sales, and adverse event reports. The following are two potential approaches to

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 FRAMEWORK TO REVIEW THE SAFETY determining the safety (or efficacy) of these products. Recognizing that both of these approaches (i.e., determining the safety of a total product or determining the safety of individual ingredients) have advantages and disadvantages, the application of either approach to evaluate the safety (and efficacy) of multi-ingredient products should be the prerogative of the military. Among other factors, the military should consider the strength of detected signals, prioritization of research gaps, and availability of re- sources. For either approach, there will be additional staff support required to maintain continuous surveillance of multi-ingredient products, including all the possible interactions. Determining total product safety Given the virtual absence of data on multi-ingredient products, the military could decide to conduct research with study designs addressing military subpopulations and environments of interest, an approach that would be both expensive and time-consuming. In addition, the rapid turnover of products in the market may make it difficult or impractical to keep such research current. Determining ingredient safety The level of concern (or efficacy) associated with the consumption of a multi-ingredient product could be determined by examination of each individual ingredient and of each potential interac- tion using the approach recommended in this chapter. The challenges in this case relate not only to the ingredients themselves but to the potential interactions among ingredients in the product. Furthermore, safety data on ingredient interactions are typically unavailable. Presence of Contaminants The linking of an adverse event to the use of a dietary supplement ingredient might be confounded if the product contains adulterants or contaminants. Attribution of the source of the adverse event becomes a formidable task. If enforced, the newly adopted cGMP rule should mini- mize the potential for inclusion of adulterants or contaminants. Because this rule will not be implemented until June 2008, its effectiveness remains to be evaluated. OVERALL RECOMMENDATIONS The committee recommends that the military use the proposed frame- work, modified from the 2005 IOM report framework, to determine whether a dietary supplement requires that military leadership take specific management actions to ensure optimal readiness and health protection of military personnel. This framework provides a methodology with a pre-

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 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL established search strategy for generating a safety monograph for a dietary supplement, and a consistent format that provides key information which can be used to assist military policy makers. It also provides criteria to initiate safety reviews based on signals generated from an adverse event; or proactively, based on significant changes in dietary supplement consump- tion by military personnel. The following are overall recommendations related to the application of the framework: • Determination of the level of concern for a dietary supplement should be based on published reviews of general safety concerns and on adverse effects and/or benefits specific to the military; the final integrated concern level should be predicated on safety concerns, modified by potential benefits, and based on special mission requirements and environments. • The final, integrated concern level and the need for dietary supple- ment management should be determined in the context of specific subpopu- lations of the military and based on their special mission requirements, environments, and locations. This analysis should pay particular attention to military subgroups of interest for whom benefits and safety are of op- erational concern. • Dietary supplement management should be predicated on safety concerns, modified by any proven benefits. • A future task force or committee should more fully describe the process and framework to characterize the efficacy of dietary supple- ments of interest to the military and describe a detailed process to monitor the emergence of dietary supplements that could provide benefits to the military. • To determine whether the level of concern for a dietary supple- ment should be reclassified as future research unfolds, research should be monitored on an annual basis, especially for those supplements for which a concern level could not be established due to lack of data. Based on rec- ommendations of the designated oversight committee, the military might also decide to support or conduct research on a specific dietary supplement depending on its relevance to the military. For example, dietary supple- ments of military interest that are classified as being of high concern based on equivocal animal data could be referred to the research community to more fully characterize the level of concern in humans. It may or may not be appropriate for the military commander to recommend that the dietary supplement not be used by military personnel until that determination has been made.

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 FRAMEWORK TO REVIEW THE SAFETY REFERENCE IOM (Institute of Medicine). 2005. Dietary supplements: A framework for ealuating safety. Washington, DC: The National Academies Press.