2
Approaches Used by Others to Consider Dietary Supplement Safety and Other Existing Safety Frameworks

The safety and efficacy of dietary supplement ingredients have been considered by a number of organizations, each of which has a framework or methodology for reviewing dietary supplements. A review of these methods was the first step in developing a framework useful to the Food and Drug Administration (FDA) for prioritizing and evaluating the safety of dietary supplement ingredients. Given that these organizations have considered different aspects of dietary supplement ingredients, it was important to consider the relevance of the methods or frameworks they have used to organize and review dietary supplement safety issues. Similarly, frameworks and methodologies have been developed for reviewing the safety of other types of substances: in foods, in pharmaceuticals, and in the environment. These are also reviewed to identify aspects that might be applicable to developing a framework for the safety evaluation of dietary supplement ingredients. Based on the above reviews, discussion in open sessions with many individuals, and the consensus of the committee, attributes of an ideal framework for setting priorities and evaluating dietary supplement ingredients were developed.

OTHER APPROACHES FOR CONSIDERING DIETARY SUPPLEMENT SAFETY

Several organizations have compiled information on the safety, efficacy, or quality of dietary supplements. To aid in the development of the framework in this report, samples of these materials were used to construct an overview of the approaches taken by these organizations. The approaches are described briefly below and in Table 2–1; more detailed descriptions are provided in Appendix A. The Appendix is based on the information provided by the organizations or in published descriptions of their approaches. Inclusion on this list does not constitute endorsement of these sources of information, nor should the list be considered exhaustive of all efforts to consider safety, efficacy, and/or quality of dietary supplements. The committee chose to focus its review on approaches that seemed to be the products of organization-sponsored or government-sponsored committee efforts or a peer-reviewed process. Additional publications, although not reviewed by the committee, might also be informative (Foster and Tyler, 1999; Grieve, 1996).



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For Comment: Proposed Framework for Evaluating the Safety of Dietary Supplements 2 Approaches Used by Others to Consider Dietary Supplement Safety and Other Existing Safety Frameworks The safety and efficacy of dietary supplement ingredients have been considered by a number of organizations, each of which has a framework or methodology for reviewing dietary supplements. A review of these methods was the first step in developing a framework useful to the Food and Drug Administration (FDA) for prioritizing and evaluating the safety of dietary supplement ingredients. Given that these organizations have considered different aspects of dietary supplement ingredients, it was important to consider the relevance of the methods or frameworks they have used to organize and review dietary supplement safety issues. Similarly, frameworks and methodologies have been developed for reviewing the safety of other types of substances: in foods, in pharmaceuticals, and in the environment. These are also reviewed to identify aspects that might be applicable to developing a framework for the safety evaluation of dietary supplement ingredients. Based on the above reviews, discussion in open sessions with many individuals, and the consensus of the committee, attributes of an ideal framework for setting priorities and evaluating dietary supplement ingredients were developed. OTHER APPROACHES FOR CONSIDERING DIETARY SUPPLEMENT SAFETY Several organizations have compiled information on the safety, efficacy, or quality of dietary supplements. To aid in the development of the framework in this report, samples of these materials were used to construct an overview of the approaches taken by these organizations. The approaches are described briefly below and in Table 2–1; more detailed descriptions are provided in Appendix A. The Appendix is based on the information provided by the organizations or in published descriptions of their approaches. Inclusion on this list does not constitute endorsement of these sources of information, nor should the list be considered exhaustive of all efforts to consider safety, efficacy, and/or quality of dietary supplements. The committee chose to focus its review on approaches that seemed to be the products of organization-sponsored or government-sponsored committee efforts or a peer-reviewed process. Additional publications, although not reviewed by the committee, might also be informative (Foster and Tyler, 1999; Grieve, 1996).

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For Comment: Proposed Framework for Evaluating the Safety of Dietary Supplements TABLE 2–1 Key Components of Approaches Used by Other Organizations to Evaluate Dietary Supplements Organization Purpose of Evaluation Selection and Types of Substances for Review Product Endpoints Agency for Healthcare Research and Quality Effectiveness Safety Variety of types Reports done at request of other agencies and organizations Summary report U.S. Pharmacopeia-National Formulary (USP-NF) Quality Variety of types Selection based on: Safety Extent of use Assessment by pharmacognosists Ability to meet USP-NF monograph requirements Evidence of historical use in traditional medicine Monographs in USP or NF USP Dietary Supplement Verification Program Quality Variety of types Selection is via manufacturer sponsorship USP certification mark or no mark American Herbal Pharmacopoeia Effectiveness Quality and analytical methods Safety Botanicals commonly used in the United States Selection based on: Recommendations of a prioritization committee (professional herbalists, herbal industry, and herbal educators) Monograph sponsorship (interested organizations or companies) Selection by other groups Summary monographs American Herbal Products Association Safety Botanical ingredients sold in North America Classification as Class 1, 2, 3, or 4 Natural Medicines Comprehensive Database Effectiveness Safety Variety of natural medicines sold in the United States and Canada Summary monographs Safety assessment classification: Likely safe Possibly safe Possibly unsafe Likely unsafe Unsafe World Health Organization Effectiveness Safety Quality Botanicals Selection based on extent of use, worldwide importance, and availability of data Summary monograph

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For Comment: Proposed Framework for Evaluating the Safety of Dietary Supplements Organization Purpose of Evaluation Selection and Types of Substances for Review Product Endpoints Commission E Effectiveness Safety All medicinal plants and phytomedicines in the German marketplace Summary monographs classified as: Positive (approved) Negative (unapproved) Negative-null (unapproved) Health Canada Natural Health Products Directoratea Safety Quality Effectiveness Vitamin and mineral supplements, botanical products, homeopathic preparations, and traditional Chinese, Ayurvedic, and native North American medicines Authorization for sale/product license European Scientific Cooperative on Phytotherapy Effectiveness Safety Phytomedicines used within the European Community Summary monographs a The Health Canada regulatory framework for natural health products is proposed—not finalized. Agency for Healthcare Research and Quality The Agency for Healthcare Research and Quality (AHRQ), a branch of the U.S. Department of Health and Human Services, is in the process of producing “evidence-based reports” for a limited number of dietary supplements. The evidence reports include information on safety and efficacy and are developed using a systematic analysis of the relevant scientific data that employs a weighting/ranking methodology to consider the data and well-defined criteria for making judgments. AHRQ has contracted this work to several institutions referred to as Evidence-based Practice Centers. Reports on garlic and milk thistle have been released and a report on ephedra is in development (AHRQ, 2002). These reports are designed to differentiate the types of evidence and the strength of the evidence. Due to the exhaustive nature of the reports, they are resource intensive. U.S. Pharmacopeia-National Formulary The U.S. Pharmacopeia-National Formulary (USP-NF), a nongovernment, nonprofit organization, develops monographs on standards of identity, strength, quality, purity, packaging, and labeling of drugs sold in the United States. These monographs are not focused on the inherent safety of the substance.8 The USP standards are recognized by Congress in the Federal Food, Drug, and Cosmetic Act of 1938 (21 U.S.C. § 321 et seq.) as the official compendium of the United States, making its established standards for drugs essentially similar to federal regulations (USP, 2002a). 8   From 1995 to 1998, USP developed prototype information monographs on several botanicals, in addition to standards monographs. Subsequently, an information monograph addressing the safety and efficacy of saw palmetto was published on the Internet in 2000. Dietary supplement information monographs are no longer produced due to lack of funding (Personal communication, S.Srinivasan, USP, June 19, 2002).

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For Comment: Proposed Framework for Evaluating the Safety of Dietary Supplements In 1990 USP-NF decided to include monographs for vitamins and minerals and in 1995, after passage of the Dietary Supplement Health and Education Act, USP-NF decided to include monographs for botanical dietary supplements (CRN, 1998). The criteria for identification and prioritization of botanicals for monograph development include absence of safety concerns, extent of use by consumers, interest from regulatory agencies, positive assessment by recognized pharmacognosists, and suitability of the botanical preparation for meeting typical requirements of USP-NF monographs (USP, 2000a, 2002b). Depending on its approval status, botanical monographs are admitted either to the USP or to the NF. A botanical monograph is placed in the USP if the botanical has an FDA- or USP-approved use. Otherwise, it is placed in the NF. Monographs are not developed for botanical dietary supplements that the USP believes may be associated with a significant safety risk (USP, 2000a, 2002b). U.S. Pharmacopeia Dietary Supplement Verification Program Distinct from its development of the USP-NF monographs, USP launched the Dietary Supplement Verification Program (DSVP) in November 2001. The program identifies dietary supplement products that contain all the ingredients listed on their product labels. Manufacturers sponsor products that are tested and reviewed by USP; if the product meets the DSVP requirements, the product will be granted a USP certification mark. This mark is intended to signify that the product (1) contains the ingredients stated on the label in the declared amount and strength, (2) meets stringent standards for product purity, (3) meets specified limits on known contaminants, and (4) has been manufactured under good manufacturing practices according to the USP-NF General Chapter on Manufacturing Practices for Nutritional Supplements and the FDA’s Advance Notice of Proposed Rulemaking for good manufacturing practices (Personal communication, S.Srinivasan, USP, February 14, 2002; USP, 2001). The DSVM certification mark is not intended to imply safety or efficacy of dietary supplement ingredients. Other organizations are also undertaking similar efforts to verify label contents, such as ConsumerLab (http://www.consumerlab.com/) and the National Science Foundation International (http://www.nsf.org/consumer/consumer_dietary.html). American Herbal Pharmacopoeia The American Herbal Pharmacopoeia (AHP), a nonprofit organization, develops monographs on the quality, effectiveness, and safety of botanical medicines commonly used in the United States. The monographs, developed for Ayurvedic,9 Chinese, and Western botanicals, include information on traditional use and information from scientific sources (CRN, 1998). Botanicals are selected for monograph development based on judgment about the extent of use, the unique value of the botanical, and sponsorship by other interested organizations or companies (AHP, 2002). In preparing the monographs, literature searches are conducted in order to review reported side effects, contraindications, and negative interactions of a botanical. AHP monographs are relatively detailed compared to monographs produced by other organizations. They are released individually as they are completed; 12 have been released since 1994 (AHP, 2002). 9   Ayurvedic is a complex system of health care that includes diet and lifestyle practices (i.e., meditation, yoga, and herbs) in order to maintain the body’s equilibrium. Ayurvedic medicines are derived from plants and are used in conjunction with modern medicine for health maintenance and restoration (Chopra and Doiphode, 2002).

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For Comment: Proposed Framework for Evaluating the Safety of Dietary Supplements American Herbal Products Association The American Herbal Products Association (AHPA), a national trade association for the herbal products industry, published The Botanical Safety Handbook in 1997. This book reviewed approximately 500 herbs that were on the market in the United States (McGuffin et al., 1997). The focus of the reviews in this book is on safety, and entries include data on human and animal toxicity, traditional use, regulatory status in various countries, and current use of herbs in the United States, China, India, Europe, and Australia. The AHPA safety classification system consists of four safety classes: Class 1 botanicals that can be safely consumed when used appropriately, Class 2 botanicals for which certain restrictions apply, Class 3 botanicals for which significant data exist to recommend special labeling, and Class 4 botanicals for which there is insufficient data for classification. Natural Medicines Comprehensive Database The Natural Medicines Comprehensive Database (NMCD) is published by Pharmacist’s Letter and Preserver’s Letter. This database reviews many “natural medicines” on the market in North America, reviewing safety and efficacy for a large number of dietary supplement ingredients. Information on the different substances reviewed is available by subscription online and in printed version (NMCD, 2002). According to the organization, the safety evaluation relies primarily on human data, and animal data are rarely used (Personal communication, P.Gregory, NMCD, November 21, 2001). Each product is rated as: (1) likely safe (general agreement among reliable references that the product is safe when used appropriately, or a governmental body has approved its use), (2) possibly safe (product might be safe when used appropriately or there are human studies that report no serious adverse effects), (3) possibly unsafe (some data suggest that product use might be unsafe), (4) likely unsafe (agreement among reputable references that the product can be harmful or reliable reports of harm), or (5) unsafe (general agreement among reliable references that the product should not be used, reliable reports of clinically significant harm, or safety warnings issued by a reliable agency). World Health Organization The World Health Organization (WHO) has developed international specifications for the most widely used medicinal plants, a number of which are also used as dietary supplements in the United States. WHO published its first volume of 28 monographs on selected medicinal plants and is in the process of publishing two additional volumes. The monographs contain information on the safety, effectiveness, and quality control of botanical medicines (WHO, 1999). Specifically, they present descriptive information, purity tests, chemical constituents, medicinal uses, clinical studies, pharmacology, contraindications, warnings, precautions, adverse reactions, and posology. The medicinal plants in the compilation are not categorized on the basis of safety. Commission E The Commission E was a 24-member committee established in 1979 by the German Minister of Health to review botanical drugs and preparations from medicinal plants. Over a period of about 15 years Commission E reviewed more than 300 botanicals used in German folk medicine for both safety and effectiveness using scientific literature, unpublished proprietary data

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For Comment: Proposed Framework for Evaluating the Safety of Dietary Supplements submitted by manufacturers (chemical, toxicological, pharmacological, and clinical testing data), summaries produced by an umbrella organization of approximately 120 pharmaceutical manufacturers, and public input (Blumenthal, 1998; Personal communication, H.Schilcher, Commission E, March 19, 2002). The published monographs do not include references and are relatively short. Each monograph provided one of three approval ratings for the substance reviewed: (1) positive (approved—substance is considered reasonably safe when used according to the dosage, contraindications, and other warnings specified in the monograph), (2) negative (unapproved—safety concerns outweigh the potential benefits of a substance), or (3) negative-null (unapproved—no risk was found, but also no substantiation of efficacy). The Commission E monographs are published in German, and the American Botanical Council has published them in English (Blumenthal, 1998). Additional information about Commission E is included in Appendix A. Health Canada Natural Health Products Directorate In Canada vitamin and mineral supplements, botanical products, homeopathic preparations, and traditional Chinese, Ayurvedic, and native North American medicines are considered to be natural health products (NHPs). At present, these products are regulated as either foods or drugs. In response to consumer demand both for enhanced access to natural health products and for assurances of safety and quality, the Natural Health Products Directorate was established within Health Canada. The Directorate has developed a proposed regulatory framework for NHPs, which would be considered a subset of drugs under the Food and Drugs Act. The NHP Regulations were published for comment in December 2001 (Department of Health, 2001). The main components of the NHP Regulations are definitions and requirements for product licensing, site licensing, good manufacturing practices, clinical trials, packaging, labeling, and reporting of adverse reactions. Under product licensing, each NHP sold in Canada will undergo an assessment before it is authorized for sale. The application for a product license would be required to provide specific information about the NHP, including the quantity of medicinal ingredients it contains, the specifications, the intended use or purpose, and supporting safety and efficacy data. Most relevant to the consideration of dietary supplement ingredient safety, the directorate has not released standards of evidence for safety for public comment. European Scientific Cooperative on Phytotherapy The European Scientific Cooperative on Phytotherapy (ESCOP) is an umbrella organization of national associations for phytotherapy from countries both within and beyond the European Union. The Scientific Committee of ESCOP, a subgroup of delegates from participating member countries, has created monographs on the medicinal uses and safety of medicinal plants widely used in Europe (information on quality is not included). The monographs are published as fascicules, each containing 10 monographs; 6 fascicules on 60 botanicals have been completed (ESCOP, 2001). The Physician’s Desk Reference for Herbal Medicines and the Physician’s Desk Reference for Nutritional Supplements In 1998 the Physicians’ Desk Reference (PDR) organization broadened its scope from producing a widely used collection of information on prescription drugs by also producing a

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For Comment: Proposed Framework for Evaluating the Safety of Dietary Supplements collection of information on botanical medicines. This publication was the first edition of the PDR for Herbal Medicines, which provides monographs for approximately 700 medicinal herbs. The monographs contain information on efficacy, safety, potential interactions, precautions, adverse reactions, and dosage. For 300 of these monographs, the findings and assessments were taken from the German Commission E report. Other monographs, as well as the reports of another PDR publication, the PDR for Nutritional Supplements, do not appear to be the products of the type of committee effort or to involve the type of peer-review process envisioned as ideal by the committee. ANALYSIS OF DIFFERENT APPROACHES TO DIETARY SUPPLEMENT EVALUATION By reviewing the approaches other groups have taken to consider dietary supplements, the observations that follow about positive and negative attributes of each approach have influenced the development of the proposed framework and system for preparing safety monographs. The type of information evaluated and the purpose of the review varied substantially from organization to organization. Most notably, the USP verification program focused on quality, specifically determining if the ingredients in a product were prepared according to good manufacturing practices, and verifying that the label matched the contents. Although USP indicated that it would consider whether a substance was safe in deciding whether or not to accept it into the program, there seemed to be less methodical emphasis on the inherent safety of the ingredients. Several other organizations placed emphasis on whether the ingredient was efficacious—a worthy objective, but one that fell outside of this committee’s charge. Most of the approaches reviewed were focused exclusively on botanical ingredients or products, rather than on dietary supplements of all types. The charge to this committee was to include all types of dietary supplements in its efforts. Perhaps most notably, the approaches considered did not describe a systematic method of determining which ingredients needed immediate attention first, a key component of the PDA’s charge to the committee. AHPA’s Botanical Safety Handbook, the Natural Medicines Comprehensive Database, and the Commission E monographs are three examples of monograph collections that did sort ingredients into several categories (e.g., approved, unapproved, possibly safe). These approaches, however, sorted ingredients into several categories after reviewing collected data, rather than sorting all ingredients by relative priority before undertaking an exhaustive evaluation of the data—as the proposed framework is charged with accomplishing. A number of the sample monographs considered were not sufficiently detailed or adequately transparent to give a complete picture of the data types and sources considered, the rationale behind the conclusions, and/or the remaining unanswered questions about safety. Monographs from several organizations were brief, without an adequate description of the different types of available data. Without substantial detail in the monograph, it was not always clear as to how or why a conclusion about the safety of the ingredient was reached. Understandably, considering the “weight of the evidence” requires expert judgment to a certain degree, but it was not always apparent what role expert opinion and experience played. The information that forms the basis for the Commission E monographs, for example, is kept confidential and includes proprietary data. In the committee’s judgment, it is important that the process be transparent and the bases of judgments be clearly described and consistently applied to the fullest extent possible, including providing opportunities for public input from industry,

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For Comment: Proposed Framework for Evaluating the Safety of Dietary Supplements scientists, and other interested parties. Also important is a description of where the scientific data may be difficult to interpret and where questions about safety remain unanswered. Another observation is that most of the reviews focused on ingredients, rather than on specific products or combinations of ingredients. An exception is that the USP verification program, which focuses on specific products because USP is paid to look at specific products by manufacturers. Commission E is another exception—it considered the safety of fixed combinations of botanical products, an important approach given the widespread marketing of combinations (Blumenthal, 1998). Similarly, analysis of specific products was outside the committee’s charge—it was to focus instead on how to consider the safety of different dietary supplement ingredients and to note how to approach a product containing a combination of ingredients. ATTRIBUTES OF AN IDEAL FRAMEWORK FOR EVALUATING DIETARY SUPPLEMENTS There are numerous frameworks in place that FDA and other organizations can use to evaluate the safety of substances to which humans may be exposed. Assessment of the scope, characteristics, and processes used for other substances can aid in the development of a workable framework for dietary supplement safety evaluation. The committee considered frameworks FDA already had in place to evaluate food additives and pharmaceuticals, as well as the mechanisms other organizations use in working with FDA when considering the safety of cosmetic ingredients, food additives generally regarded as safe (GRAS), and nutrients. The Environmental Protection Agency has also developed a system for considering possible human and environmental impacts of toxic substances. Table 2–2 provides a brief summary of the nondietary supplement frameworks considered; more detailed summaries of the different approaches, as described by the organizations, are in Appendix B. In considering frameworks used to evaluate the safety of substances other than dietary supplements, the committee developed an understanding of different types of “frameworks” and how they differed from other methods that might be used to evaluate dietary supplements. To this end, the committee developed a definition of a “framework” for safety evaluation of dietary supplement ingredients as follows: “The processes by which FDA can screen, categorize, and evaluate available information to make scientifically documented regulatory decisions regarding dietary supplement ingredients for consumers.” In reviewing the methods used by other expert bodies to consider dietary supplements and in reviewing the discussions with the sponsors and other interested representatives, the following attributes of an ideal framework were identified: it must be workable and able to be integrated into the agency’s program of work and resources available; it should provide guidance to organizing diverse information already available; it should categorize the diverse substances classified as dietary supplements based on a scientifically valid metric; it should establish a database for collection of information regarding potential safety concerns that can be updated as new information is available;

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For Comment: Proposed Framework for Evaluating the Safety of Dietary Supplements TABLE 2–2 Safety Review Systems for Nondietary Supplement Substances Purpose of Review Organization Type of Organization Endpoints Premarket safety evaluation of food ingredients/food additives Food and Drug Administration/Center for Food Safety and Applied Nutrition Government Approved Approval with limitations Interim approval Disapproval Safety evaluation of food additives/food ingredients generally recognized as safe (GRAS) in 1972 Select Committee on GRAS Substancesa Nongovernment/ nonindustry Continue as GRAS Continue as GRAS with limitations Further testing required Evidence of adverse effects—may remove GRAS status if safety not established Remove GRAS status Safety evaluation and determination of GRAS status of flavor ingredients Flavor and Extract Manufacturers Association (FEMA) Expert Panel Industry GRAS status Not GRAS Insufficient data to determine GRAS status Safety assessment of cosmetic ingredients Cosmetics Ingredient Review Program Industry Safe as used Safe with qualifications Unsafe Insufficient data Premarket evaluation and approval of new drugs Food and Drug Administration/Center for Drug Evaluation and Research Government Approved Not approved Over-the-counter (OTC) Drug Review to establish conditions under which OTC drugs would be considered generally recognized as safe and effective (GRAS/E) Food and Drug Administration Government Category I (GRAS/E) Category II (not GRAS/E or unacceptable indications) Category III (insufficient data) Regulation of entry and use of new chemicals in the marketplace; assessment of human and environmental risk of new chemicals Environmental Protection Agency New Chemicals Program Government No action taken to regulate the chemical More testing needed Determination of the Tolerable Upper Intake Level (UL) for nutrientsb Institute of Medicine/Food and Nutrition Board Nongovernment/ nonindustry UL Scientific evidence insufficient to set UL a Source: Select Committee on GRAS Substances (1982). b Note that nutrients are in many cases dietary supplements or dietary supplement ingredients; this safety framework, however, only applies to nutrients and recognized food components thought to play a role in health.

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For Comment: Proposed Framework for Evaluating the Safety of Dietary Supplements it should provide a method to integrate diverse information into a priority-setting scheme so that efforts and resources can be maximally directed toward those dietary supplement ingredients with the greatest safety concerns; and it should provide a mechanism for public input. Once the definition and key attributes of a safety framework were understood and the committee had an understanding of approaches taken by other expert groups, the committee then developed a framework focused on the safety of dietary supplements. This approach is outlined briefly in the following chapter, with additional detail in succeeding chapters. REFERENCES AHP (American Herbal Pharmacopoeia). 2002. American Herbal Pharmacopoeia and Therapeutic Compendium: Standards of Analysis, Quality Control, and Therapeutics. Online. Available at http://www.herbal-ahp.org/. Accessed June 19, 2002. AHRQ (Agency for Healthcare Research and Quality). 2002. Evidence-based Practice Centers. Online. Available at http://www.ahrq.gov/clinic/epc/. Accessed June 17, 2002. Blumenthal M, ed. 1998. Therapeutic Guide to Herbal Medicines. The Complete German Commission E Monographs. Austin, TX: American Botanical Council. Chopra A, Doiphode VV. 2002. Ayurvedic medicine. Core concept, therapeutic principles, and current relevance. Med Clin North Am 86:75–89, vii. CRN (Council for Responsible Nutrition). 1998. Reference on Evaluating Botanicals. Washington, DC: CRN. Department of Health. 2001. Natural health products regulations. Canada Gazette, Part I 135:4912–4981. ESCOP (The European Scientific Cooperative on Phytotherapy). 2001. Publications. ESCOP Monographs. Online. Available at http://www.escop.com/publications.htm. Accessed November 12, 2001. Foster S, Tyler VE. 1999. Tyler‘s Honest Herbal. A Sensible Guide to the Use of Herbs and Related Remedies. 4th ed. New York: Haworth Herbal Press. Grieve M. 1996. A Modern Herbal. New York: Barnes and Noble. McGuffin M, Hobbs C, Upton R, Goldberg A. 1997. American Herbal Product Association’s Botanical Safety Handbook. Boca Raton, FL: CRC Press. NMCD (Natural Medicines Comprehensive Database). 2002. About the Database. Online. Available at http://www.naturaldatabase.com/aboutdb.asp. Accessed January 7, 2002. Select Committee on GRAS Substances. 1982. Insights on Food Safety Evaluation. Rockville, MD: Life Sciences Research Office. USP (The United States Pharmacopeia). 2001. USP Board of Trustees Agrees to Continue Proceeding with Pilot Program for Dietary Supplement Verification. Online. Available at http://www.usp.org. Accessed October 31, 2001. USP. 2002a. USP 25-NF 20. Rockville, MD: United States Pharmacopeial Convention, Inc. USP. 2002b. USP Fact Sheet. Online. Available at http://www.usp.org. Accessed June 18, 2002. WHO (World Health Organization). 1999. WHO Monographs on Selected Medicinal Plants, Volume I. Geneva: WHO.