Toxicology of Dietary Supplements
National Capital Area Chapter Society of Toxicology
National Capital Area Chapter Society for Risk Analysis
November 2, 2004
Speaker Abstracts and Slide Presentations
Botanical Dietary Supplements: Perspectives
School of Pharmacy, The University of Mississippi
Plants comprised the main source of medicinal agents for most of the history of man, and plant-derived natural products shaped many of the basic constructs of our modern disciplines of pharmacology and toxicology. Much of the emphasis on natural products waned in the middle of the 20th century, the ‘age of chemistry’, when it was envisioned that synthesis of ‘magic bullets’ would make natural medicines obsolete. Crude botanical drugs largely disappeared from western medicine, and until the 1990s were relegated to health food stores and herbalists’ shops. In 1994, with the passage of the Dietary Supplement Health and Education Act, a regulatory context was set for ‘herbal products’ that considered botanicals as food supplements as opposed to drugs; this ushered in a decade of robust growth in the widespread and relatively unregulated use of botanicals. Proponents argue that many traditionally used and beneficial products are now readily available. Opponents contend that unproven, and in some instances unsafe, products are widely distributed, aggressively marketed, and ill-used, resulting in unnecessary risks. Sorting out the real risks and benefits is complicated because of the complexity and variability of botanical mixtures. This talk will focus on key developments that shaped the current environment, illustrations of the nature and complexity of toxicological problems with botanicals, and a look at the future of botanical medicines.
Synergism, Antagonism, or Additivity of Dietary Supplements
Christopher J. Borgert
Applied Pharmacology & Toxicology, Inc.
Interactions between dietary supplements, nutraceuticals, functional foods and drugs are possible but probably not prevalent. The literature provides a base of information from which to begin an analysis of the likely incidence and severity of interactions between these various agents, but several caveats must be kept in mind. Reported interactions are not always relevant to clinical experience. Many reported interactions are based on flawed study designs that cannot support the interpretations and conclusions drawn from the data. A critical analysis of reported interactions among dietary supplements reveals the difficulties inherent in assessing interaction dose-response, interaction thresholds, and magnitude of interactive effects. These concepts, however, will be critical to developing a rational path forward for assessing potential interactions among dietary supplements, nutraceuticals, functional foods and drugs. Essential information for such assessments includes data demonstrating the mechanisms by which broad classes of clinically relevant interactions can occur and the available pharmacological, toxicological and mechanistic information on the products being assessed.
Speaker presentation available (Adobe Acrobat)
Natural Toxins in Botanical Products
Joseph M. Betz
National Institutes of Health
Impurities in botanical products may be microbiological, botanical, and non-botanical. Means of measuring microbial loads, pesticides, mycotoxins, and toxic elements in foods are reasonably well established, and extension into dietary supplements should be reasonably straightforward. Determination of natural toxins or synthetic drugs in botanical raw materials and finished products may be more problematic.
There are two scenarios surrounding impurity analysis that pose particular challenges to the QA/QC manager. The first is presence of a toxic constituent known to occur naturally in the ingredient. An example is the occurrence of pyrrolizidine alkaloids (PA) in comfrey. These compounds are known hepatotoxins and toxicity is thought to be cumulative. European authorities limit PA content of plant material to 1 ppm, Canada’s Natural Health Products Directorate has prohibited sale of Russian comfrey as a Natural Health Product, and the FDA has expressed concern about products that contain these compounds. Pyrrolizidine alkaloids in “PA free” products could reasonably be called impurities. Since the identities of the impurities are known, this would seem to be a straightforward problem for the analyst. The challenges are a lack of commercially available analytical standards and a dependence on risk assessors to establish the requirements for sensitivity, specificity, and accuracy of the method. If the regulatory authorities establish a “zero tolerance” policy, the method will have to be pushed as hard as possible to achieve the best available sensitivity. Specificity and accuracy will also need to be carefully established for economic and regulatory reasons.
The second scenario is detection and quantitation of plant toxins that are present in the botanical product because the wrong plant or plant part has been substituted for or added to the intended ingredient. Contamination with the “wrong” plant may be accidental or intentional, and the “needle in a haystack” aspects of the challenge are ameliorated somewhat if there is a history of a particular type of contamination associated with a particular ingredient. An example of this is the substitution of Aristolochia fangchi for Stephania tetrandra. Dealers in Stephania would be well advised to have systems in place for the detection of the nephrotoxic aristolochic acids that are known to occur in Aristolochia spp. Contamination of the intended ingredient with some extraneous plant material such as a weed or weed seed (especially in small amounts) is the ultimate challenge for the analyst. General approaches to ensuring purity of botanical products range from establishing identity of raw materials by physical inspection to genetic or chromatographic fingerprinting to determination of specific toxic constituents by LC/MS or GC/MS. Limitations include a lack of analytical standards for known compounds, lack of widely available methodology, and lack of spectral databases for natural toxins.
The Roles of the Nuclear Receptors PXR and CAR in Xenobiotic Response
John T. Moore
Glaxo Smith Kline
The nuclear receptors PXR (NR1I2) and CAR (NR1I3) are activated by an overlapping set of ligands, regulate a subset of common genes, and signal through the same response elements. Both receptors have been proposed to function as xenosensors, but the details of their respective roles are still being elucidated. We have contrasted these two receptors in a variety of experiments including gene expression arrays, cell-based ligand profiling assays, and crystallographic/structural modeling analyses in order to further differentiate their physiological roles. Affymetrix gene array studies revealed that CAR and PXR regulate overlapping but distinct gene expression pathways. Generally, both receptors regulated genes involved in xenobiotic metabolism including phase I, phase II, and transporter genes, but distinct differences in their gene expression profiles were evident within each of these categories. Notably, we linked the changes in gene expression to a distinct role for CAR in response to nutritional stress. Physiological measurements in CAR knock-out animals supported the model suggested by the gene expression data. These studies extend the physiological role of CAR beyond xenobiotic protection. Finally, we provide evidence that the unique structures and ligand activation characteristics of CAR and PXR reflect their contrasting physiological roles.
Regulatory Framework for Dietary Supplements
Linda S. Pellicore
U.S. Food and Drug Administration
Section 413 of the act sets forth the requirements that must be met by dietary supplements containing certain new dietary ingredients. Section 413(c) of the act defines the term new dietary ingredient to mean a dietary ingredient that was not marketed in the United States before October 15, 1994. Section 413(a) of the act provides that a dietary supplement which contains a new dietary ingredient shall be deemed adulterated under section 402(f) unless it meets one of two requirements: (1) it contains only dietary ingredients which have been present in the food supply as an article used for food in a form in which the food has not been chemically altered; or (2) there is a history of use or other evidence of safety establishing that the new dietary ingredient, when used under the conditions recommended or suggested in the labeling of the dietary supplement, is reasonably expected to be safe and, at least 75 days before being introduced or delivered for introduction into interstate commerce, the manufacturer or distributor of the dietary ingredient or dietary supplement provides the Secretary (and by delegation, FDA) with information, including any citation to published articles, which is the basis on which the manufacturer or distributor has concluded that a dietary supplement containing such dietary ingredient will reasonably be expected to be safe.
Industry Perspective on the Toxicology of Dietary Supplements
Dietary supplement toxicology is a subset of the toxicology of natural products. Sometimes segments of the academic community do not attend to basic principles when reviewing materials sold as dietary supplements. This apparent bias emerges when questions of toxicity are raised without regard to proper identification of materials, the known phytochemistry of particular botanicals, or the biological properties of specific chemicals. Nevertheless, and notwithstanding poor science from some critics, particular toxicological issues are known to exist for some dietary supplements and they require appropriate attention. This presentation evaluates some examples of speculative dietary supplement toxicity where more factual information could have resulted in a better informed approach. Industry recommendations are also provided where some known toxicological issues exist.
Speaker presentation available (Microsoft PowerPoint)
The Life Sciences Research Office Report on Recommendations for Adverse Event Monitoring Programs for Dietary Supplements
Catherine J. Klein
Life Sciences Research Office
Under the Dietary Supplement Health and Education Act of 1994, dietary supplements are regulated as a subcategory of food. Currently, there is no federal guidance or mandate for the collection, documentation, or evaluation of consumer health complaints associated with the use of dietary supplements. The Life Sciences Research Office (LSRO) made recommendations for the design and development of adverse event monitoring programs specifically tailored for dietary supplements. Adverse event monitoring programs for foods or drugs identify potential product-related health problems or signals, which are further quantified and evaluated to determine whether they represent coincidence, artifact, or a genuine problem in toxicity that might lead to changes in labeling and/or restrictions in use. LSRO convened an ad-hoc independent, expert advisory panel and divided this overall project into two phases:(1) the review and comparison of individual data records associated with the use of dietary supplements and evaluation of their usefulness for generating signals of potential product problems; and, (2) the review of postmarketing surveillance programs described in the scientific literature and recommendations for 25 minimal elements of a postmarketing surveillance program for dietary supplements, including recommendations for collecting, documenting, organizing, and analyzing adverse events. If implemented, such programs better inform risk management choices by manufacturers, regulators, and product users, and thereby reduce potential health risks from dietary supplements. This project was sponsored by Metabolife International, Inc. (San Diego, CA), through its counsel, Patton Boggs, L.L.P. (Washington, DC).
Speaker presentation available (Adobe Acrobat)
National Academy of Sciences Monograph on Dietary Supplements: A
The Committee on the Framework for Evaluating the Safety of Dietary Supplements (based on the current law as it relates to DSHEA) of the Institute of Medicine of the National Academy of Sciences, was asked by the Food and Drug Administration to develop a method for evaluating the safety of dietary supplement ingredients. The lecture will briefly describe the use of existing human, animal and in vitro data and other factors in developing the Framework.
Speaker presentation available (Microsoft PowerPoint)