“If we could give every individual the right amount of nourishment (and exercise), not too little and not too much, we would have found the safest way to health...” Hippocrates, c. 460 - 377 B.C.
The use of dietary ingredients as complementary components of the human diet for the purpose of achieving nutritional and beneficial health or therapeutic effects is of known antiquity. Proclaimed to be the founder of modern medicine, Hippocrates advocated the healthful benefits of ingredients of the diet and treated his patients with natural dietary remedies, such as apple cider vinegar, believed to possess powerful healing and cleansing qualities. The traditional use of herbs and minerals in Chinese medicine is well documented, the remedies of which include numerous varieties of herbal extracts and teas with long-professed medicinal virtues. Women of the Amazonian culture have been reported to use horsetail for the alleviation of menstrual symptoms, and Native American populations traditionally have used tea of wintergreen leaves as an antipyretic agent. The significant 18th century discovery by Dr. James Lind of the treatment of scurvy by supplementation of the diet with citrus fruits is reported to have led directly to the discovery of vitamins. Today, the widespread use in the U.S. of dietary ingredients as supplements to the traditional diet is evidenced by the numerous amounts of supplement products on the market.
Despite the intent for these products to be utilized for the purpose of providing nutritional and beneficial health effects, there have been recent high-profile reports of adverse effects purportedly attributed to the use of certain dietary supplement products. Such reports have contributed to increased scrutiny, in general, of the safety of all types of dietary supplement products, and in some jurisdictions, have prompted bans on certain dietary ingredients. Consequently, regulatory oversight of the use of these products is a contentious issue. In some jurisdictions, such as Canada and the EU (European Union), the markets for dietary supplement use are in the process of redefinition through various legislative activities regarding these products.
For decades, the U.S. Food and Drug Administration (FDA) regulated dietary supplements as food products under the 1958 amendments to the Federal Food, Drug, and Cosmetic Act (FFDCA). This allowed the FDA to evaluate the safety of all new ingredients in dietary supplements and to ensure the truthfulness of their product labeling; however, regulation in this manner was restrictive to the availability of these products to consumers. As a result, in 1994 the U.S. Congress passed the Dietary Supplement Health and Education Act (DSHEA) and amended the FFDCA to include several provisions specific to dietary supplements and ingredients thereof. The intent of Congress in ratifying DSHEA was to address the concerns of consumers and manufacturers to continue to help ensure that safe and appropriately labeled products remain available to the American population.
At the time of promulgation of DSHEA in 1994, the U.S. Congress reported that almost 50% of Americans regularly consume dietary supplement products for the purpose of improving their nutrition and health. Due to the ever-increasing interest in the potential health benefits of many of these products, it is likely that the proportion of dietary supplement users in the U.S. now exceeds 50% of the population. Market trends certainly suggest that the use of dietary supplement products is steadily increasing. In 2002, U.S. sales for dietary supplements reached $18.7 billion, a growth of nearly 4% over the previous year. The growth forecast for the supplement industry has been estimated at 3-5% over the period of 2003 through 2005. With the expected escalation in supplement product sales, it may be assumed that product use will increase and that the demographics of supplement users will widen.
The Demand of ‘Absolute Safety’
Consumers often demand assurance of “absolute safety,” which of course is unattainable. Safety can only be evaluated in the context of the use of the product, and any conclusion on the safety of dietary supplements must be based on sound and credible scientific evidence. Whether categorized as dietary supplements, natural health products or food supplements, these products are variously regulated across different jurisdictions worldwide. However, mandatory regulatory requirements aside, with the steadily increasing interest in dietary supplements and the plethora of scientific data being generated to support the potential benefits of various supplement ingredients, the underlying common thread that supports the use of these products is safety.
With the enactment of DSHEA, Congress defined dietary supplements as oral products that contain “dietary ingredients” intended to supplement the diet. Such “dietary ingredients” may include one or any combination of vitamins, minerals, herbs or other botanicals, amino acids, metabolites, and substances such as enzymes and organ and glandular tissues. An ingredient is considered a “new” dietary ingredient (NDI) if it was not marketed in the U.S. in a dietary supplement product prior to 1994. Included in the genre of foods, supplement products may be sold in many forms, such as tablets, capsules, soft gels, gelcaps, liquids, powders, and even bars, provided they are not represented as a conventional food item or as a sole item of a meal or of the diet, and every dietary supplement product is labeled as such. The provisions of DSHEA, however, negate the requirement for premarket safety evaluation of dietary ingredients used in supplement products (unless considered NDIs), although other safety provisions must still be satisfied.
In February 2003, Senator Richard Durbin (D-IL) introduced Federal Senate Bill S. 722, the “Dietary Supplement Safety Act of 2003.” Under the proposed legislation, certain supplement products containing stimulants would require pre-market approval, manufacturers would be subject to strict requirements for relaying consumer adverse event reports and the FDA would be granted broader authority to determine the adequate levels of safety for these products, and where such data are deemed inadequate, could force manufacturers to withdraw their products from the market. Bill S. 722 essentially would shift the burden of proof from the FDA to the manufacturer. In light of reported adverse events purportedly related to supplement use, it is not surprising that issues surrounding the regulation of the safety of these products have come to the forefront. The key question to the supplement industry remains, “What is necessary to establish safety?”
Basis for Conclusion of Safety
In the U.S., the safety of dietary supplement ingredients is determined on the basis of reasonable expectation of safety. While the semantics are debatable and other jurisdictions may simply apply a requirement for the demonstration of safety, the bottom line becomes the provision of sufficient evidence to establish safety of a supplement product. Insufficient evidence to demonstrate safety is a predominant reason for the rejection of Premarket Notifications for NDIs by the FDA.
Taking into consideration the chemistry, method of manufacture and specifications of a supplement, the requirements of good manufacturing practice (GMP) and use of industry best practices generally will capture the integrity of manufacture of the ingredient and ensure quality of a dietary supplement product. The derived specifications must meet acceptable standards and additional consideration should be given to the sources of the ingredient. For example, if a dietary ingredient is derived or extracted from a natural source, there may be other constituents present that will need to be addressed in the evaluation of safety. However, due diligence demands the availability of safety data to support use.
For many common constituents of dietary supplements, such as certain amino acids, sugars and proteins, safety can be inferred. Otherwise, safety may be concluded based on the historical use of the substance, or chemically analogous counterpart, under conditions of use relevant to those intended. This information may be supported by data from toxicological studies and from statistically valid clinical studies measuring some parameters of safety. In some instances where the existing documentation is deficient, toxicological studies may be required in order to validate the safety under the conditions of intended use.
Considerations in Evaluating Safety
Of key importance for evaluating safety is the concept of the dose-response relationship. This relationship allows for a quantitative assessment of safety and is grounded in the simple underlying principle that “the dose makes the poison.” Without question adverse effects can occur as a consequence of over-exposure to any dietary constituent. As a result, it is crucial to determine the dose that results in an adverse effect. In addition, the nature of the adverse effect identified will assist in distinguishing the specific mechanism of toxicity. This may further aid in the identification of sub-groups of the general population that may be at potentially greater risk following exposure. For example, individuals with a metabolic disorder exhibiting a deficiency in a certain enzyme required for the elimination of a substance may be identified as a particular at-risk category. In evaluating the dose-response relationship it is important to be aware of the possible distinction of toxicological effects and those that may be physiological effects, or potentially reversible effects.
The recommended dose of any ingredient of a dietary supplement is based on the intended physiological or nutritional effect of that supplement and should also represent a safe level of use. With a recommended dose clearly indicated on a label, the intended exposure is quantified and limited. However, while representing a safe level of use, the recommended dose is not intended to represent an upper level of safe use. Stated simply, the risk of adverse effects increases as the intake exceeds the recommended dose. Therefore the evaluation of safety need not establish a safety ceiling, since exceeding the recommended dose would not comply with the intended conditions of use. As a supplement to the diet, risk-benefit considerations are not a component of the overall safety evaluation of these products, as would be the case for pharmaceuticals. Thus, any supposed beneficial effects at doses that may compromise safety would not be considered acceptable.
Approaches to the Safety Evaluation
While the basis for use of a dietary supplement may rely upon common knowledge, history of use and/or experimental studies demonstrating efficacy, this basis alone may not suffice when considering safety. Evaluating the safety of dietary supplements must be approached on a case-by-case basis, depending on the nature of the supplement, the intended use and the availability of data. This evaluation can proceed in a phasic approach to avoid unnecessary expenditures of time and money. For example, recommendations to proceed with a comprehensive range of toxicological safety studies may be unjustified, without first considering the completeness of the data that may already exist to support safety under the conditions of intended use. Certain dietary supplements comprise substances with well-documented histories of use in the human diet; however, as mentioned previously, the history of use of an ingredient should relate not only to the intended conditions of use of the proposed dietary supplement, but also to the identity and composition.
In the absence of historical evidence of use, or to corroborate clinical studies demonstrating efficacy, the approach to establish safety could entail a critical review of the existing scientific literature. This approach relies upon the availability of toxicological safety data in the public domain or otherwise conducted under contract. These data may include information from animal toxicology and pharmacokinetics studies, as well as from case reports and human clinical studies. Furthermore, critical review of data available for chemically similar substances may also substantiate the data for the supplement of interest and should be incorporated into the overall safety assessment as appropriate. Care should be taken to minimize the overzealous application of reported adverse events to conclude a dietary supplement ingredient is unsafe. Causality is not possible to ascertain from such reports in light of the potential for any number of confounding factors, as well as uncertainty regarding the accuracy of the reported event, and in the absence of controls.
For those substances without sufficient documentation of safety in the literature, or elsewhere, toxicological studies may be necessary to validate safety under the conditions of intended use. The type and extent of toxicological testing that may be required for a dietary supplement ingredient cannot be generalized; however, there are some common guidelines to any study that may be commissioned. Importantly, the substance tested should be the same as that occurring in the dietary supplement. The full extent of studies necessary will depend on both the amount of pre-existing information and the intended use/recommended dose level. In some instances, animal studies may be appropriate to complete any gaps in the scientific literature, or to further define specific toxicological considerations of bioavailability and metabolism. Should a clinical study be required to substantiate safety under the intended conditions of use (i.e., for a possible at-risk population), it should be well designed and statistically valid, incorporating measurable safety parameters relevant to the physiological activity of the supplement ingredient.
Through a comprehensive search of the literature and critical review of the available scientific data, the evaluation of safety of a dietary ingredient could proceed through the recognized approach of risk assessment. Ultimately, the more rigorous the supporting scientific data, the lower the uncertainty in establishing a safe level of use. While regulatory requirements to support the intended use of a dietary supplement may vary across jurisdictions, an assessment of safety will invariably rely upon the totality of the data to establish both safe and effective doses.
About the authors: Jason Hlywka, Ph.D., and Melody Harwood, B.Sc., are scientific and regulatory consultants within the Food and Nutrition Business Group of Cantox Health Sciences International, Mississauga, Ontario, Canada. The authors may be reached at 905-542-2900; Fax: 905-542-1011; Email: [email protected]