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The Botanical Safety Consortium (BSC): The Development of a 21st Century Framework for Assessing the Safety of Botanical Dietary Supplements

Posted 25 June 2019 | By Daniel S. Marsman, DVM, PhDJoseph T. Dever, PhDStefan Gafner, PhDCynthia Rider, PhDSibyl Swift, PhDJames C. Griffiths, PhD 

The Botanical Safety Consortium (BSC): The Development of a 21st Century Framework for Assessing the Safety of Botanical Dietary Supplements

This article discusses steps to improve the safety of botanicals in dietary supplements. The authors discuss several US legislative initiatives and efforts by several nongovernmental organizations, such as the Council for Responsible Nutrition and the American Botanical Council, to track patterns of botanical use, and the Congress of the European Societies of Toxicology’s efforts to approach safety issues, including its establishment of the Botanical Safety Consortium and its working groups.
 
Introduction
 
Natural health products, often considered a safe and natural alternative to conventional medicine, have exhibited a resurgence in Western society. In the US, since the introduction of the Dietary Supplement Health and Education Act of 1994 (DSHEA),1 the dietary supplement market has flourished. Concomitantly, the dietary supplement market has further morphed into various product streams, a most rapidly expanding one being products containing one or more botanical/herbal ingredients. In parallel with this market expansion, substantial advancements in analytical methodologies have led to a better understanding of the complexity and diversity of botanical chemistry and botanical preparations. This increased knowledge has led to a growing awareness of the potential safety concerns associated with botanicals, especially their impurities, and contaminants.
 
Tracking use of Botanical Dietary Supplement Products
 
Because of the success of the dietary supplement industry and the pursuit of an ever-broadening array of products, it is not surprising the industry needed to turn greater focus toward assuring the safety of these products. For the botanical dietary supplement products, a plethora of botanical compounds are currently “in vogue” and an increasing number and diversity of botanical preparations have been incorporated into innovative multi-botanical products continually entering the market. To track their success, the Council for Responsible Nutrition (CRN) conducts an annual survey of consumer activity. Their data clearly indicate how the use of botanicals continues to grow year-by-year. For example, in 2018, their survey indicated that 75% of Americans take supplements and of those, 41% have used herbals/botanicals during the previous year.2 This represents a 13% increase for herbals/botanicals use over the last five years. Similarly, the American Botanical Council tracks consumer use patterns and has published data indicating interest in and use of herbal and other natural products has continued to rise at a substantial rate, with US sales in 2017 exceeding $8 billion dollars.3 This increased use, and the entrance into the market of newer and more ethnically focused botanicals from emerging regions and countries, such as India, China and Latin America, should be a focus of attention for those in the scientific and regulatory community charged with product stewardship and consumer safety. 
 
Safety and Testing Revisions
 
To establish the reasonable expectation of safety, companies have had to rely on outdated botanical safety frameworks. These frameworks employ the same methodologies used for discrete and pure drug compounds and other chemical moieties, and they primarily depend upon a significant number of animal toxicity tests. From a global regulatory perspective, there are essentially no specific safety tests required, allowing each manufacturer to use their own best judgment on which testing approach is needed for the New Dietary Ingredient (NDI) variant in question. Traditional premarket safety testing, with reliance on in vivo animal test methods, has become increasingly difficult for addressing botanical safety, both due to the complexity and variability of the ingredients as well as the combination of a multitude of discrete botanical ingredients into ever-increasing combinations and co-use scenarios. These concerns for testing botanicals in traditional animal studies is in addition to the many criticisms of these studies. These concerns include high-dose, non-physiologic dosing regimens, additional uncertainty factors for extrapolation to humans, significant financial and labor costs, time consumption (often in years) and the questionable ethics associated with the use of animal models. In addition to direct challenges to use of traditional pre-clinical studies, another confounding factor is the large number of potential variants of each potential botanical material due to seasonal variations, harvesting practices, processing and manufacturing differences, among others. 
 
Innovation within the dietary supplement sector often focuses on subtle—and not so subtle—“tweaks” to currently popular botanical ingredients so that different levels of marker compounds, active moieties and changes in Absorption, Distribution, Metabolism and Elimination (ADME), may be realized.  When higher concentrations of marker compounds/putative actives are achieved, safety studies may focus solely on these substances. However, it is often unclear, or unlikely, that the active constituent for nutritional efficacy is the most toxic constituent. Therefore, the traditional toxicological challenges with complex mixtures apply to botanicals. These uncertainties may include questions around synergistic or antagonistic action between botanical constituents, or actions with other botanical constituents in the mixture.
 
New Approaches for Safety Assessment
 
Given the continued interest in botanicals in a variety of consumer care products, coupled with a strong desire to minimize or eliminate animal testing and the recent developments regarding in vitro and in silico safety testing methods, the time is ripe to consider new approaches for the safety assessment of botanicals intended for use in food/dietary supplements. These approaches could include capturing adverse event data from clinical studies and postmarket surveillance, but this should be carried out by relying on new methodologies to assess specific safety endpoints. Human use data can be used as a filter to assist in the decision-making for further testing. In addition, modern analytical characterization of a botanical ingredient can be potentially coupled with a suite of endpoint evaluations to create a tiered approach to assessing toxicity based on existing data as well as new data generated specifically for safety assurance.4
 
In order to expand on the topic of botanical safety assessments, representatives from industry, academia and the regulatory community participated in a scientific session, “Botanical Safety Evaluation in the era of Alternatives” at the 53rd Congress of the European Societies of Toxicology (Eurotox 2017). This session was followed by a roundtable building on the elements shared by presenters during the scientific session. The roundtable panel and participants discussed—and provided perspective on—a “decision tree” approach (i.e., is there general alignment to the key elements that are needed to build a robust botanical safety evaluation) and inherent vulnerabilities of such an approach.5 Key elements discussed and carefully considered included the accurate identification and advanced multi-detector analytical characterization of botanical raw materials and the in silico approaches potentially used to address safety data gaps and inform the need for further studies. Other topics discussed included a discussion of scientific proof necessary to conduct similarity comparisons to commonly consumed foods or botanicals (i.e., with a well-established safety profile and a systematic evaluation of relevant toxicity data of botanical constituents utilizing structure-activity relationships. Included as well was the application of established Threshold of Toxicologic Concern (TTC) principles to botanical constituents, in the absence of data and where safety endpoint gaps are identified which cannot be resolved without in vitro or in vivo studies, and the botanical compositional data that essential to inform study design. The 2017 Eurotox session was used as a “springboard” to add these perspectives to the public discourse and the scientific literature, as evidenced by the 2018 Society of Toxicology poster presentation6 and the 2019 Toxicology Letters manuscript.7
 
The Botanical Safety Consortium
 
The scientific discourse begun at Eurotox 2017 continued at the International Conference on the Science of Botanicals (ICSB 2018). At this meeting, interested parties from industry, academia, science-based trade associations and the regulatory community came together to propose the inauguration of a pragmatic strategy to explore scientific solutions through a multifunctional collaborative, later referred to as the Botanical Safety Consortium (BSC).8,9   
 
The objective of the BSC is to provide a sound scientific basis for integrating existing botanical safety/toxicity data with the latest toxicological tools, including, but not limited to, in silico and in vitro methodologies to more thoroughly evaluate botanical safety.
 
Some of the key areas the BSC will explore include the chemical characterization of complex botanical mixtures and fit-for-purpose assays and models for evaluating genotoxicity, hepatotoxicity, developmental and reproductive toxicity, cardiotoxicity and systemic toxicity. In addition, attention also will focus on in vitro ADME and herb-drug and herb-herb interactions.  
 
A botanical library containing ingredients with known in vivo toxicity gained from animal studies or reports of adverse events in humans, will be created and evaluated in the recommended battery of assays. Results from the consortium will be shared through a publicly available database and along with findings and recommendations published in peer-reviewed literature.
 
BSC Working Groups (WGs) will address analytical characterization and key safety endpoints. The two co-chairs of each BSC WG will be technical representatives from industry and from government or academia to maintain balance. A BSC Steering Team will provide oversight and guidance to the BSC WGs. The Steering Team includes representation from a variety of dietary supplement stakeholder segments including the Federal Government as FDA’s Office of Dietary Supplement Program (ODSP), National Institute of Environmental Health Sciences (NIEHS), dietary supplement manufacturers, trade associations and other non-governmental organizations.
 
Conclusion
 
At this writing, the BSC is still in the early stages of coalescing and establishing its processes and procedures. In addition to this administrative work, the steering committee is working with the BSC WG co-chairs to identify additional scientists with specific expertise in the above-mentioned toxicologic endpoints. WG membership will be based on a capacity to carry out the work, interest, expertise and willingness to share internal data and experience in the design of future work. Active participation is an expectation in this ‘roll-up-your-sleeves’ exercise, including specific expertise in tests, assays and models to address the endpoints outlined above. The BSC WGs will be expected to provide input on the selection of candidate ingredients to be placed in the BSC’s assays and modeling exercises. There are plans to create a mechanism for stakeholder and scientific peer feedback, as well as an annual scientific meeting where information will be openly shared. Results from work undertaken by the BSC (via the targeted working group activities and data generation) will be published in the peer-reviewed literature.
 
The goal of the BSC will be to enhance the botanical safety toolkit and bring clarity to botanical safety assessments for manufacturers and regulators. With broad representation by interested and affected parties, the BSC Steering Committee and Working Groups will be designed to ensure collaborative and cooperative scientific recommendations.
 
References
 
  1. US Congress. United States Code: Federal Food, Drug, and Cosmetic Act, 21 USC §§ 301-392 Suppl. 5. 1934. https://www.loc.gov/item/uscode1934-006021009/. Accessed 17 June 2019.
  2. Council for Responsible Nutrition (CRN). Annual Survey on Dietary Supplements. 2018. Washington, DC. https://www.crnusa.org/CRNConsumerSurvey. Accessed 17 June 2019.
  3. American Botanical Council (ABC). Herbal Gram. The Journal of the American Botanical Council. 2017. Issue 119. http://cms.herbalgram.org/herbalgram/issue119/hg119-herbmktrpt.html?ts=1556561855&signature=8dfe62c7ff406bc90d9dac1d2306e361. Accessed 17 June 2019.
  4. Little JG, Marsman DS, Baker TR and Mahony C. “In silico Approach to Safety of Botanical Dietary Supplement Ingredients Utilizing Constituent-Level Characterization.” Food Chem. Toxicol. September 2017; 107 (Part A), 418-429. https://www.ncbi.nlm.nih.gov/pubmed/28698155. Accessed 17 June 2019.
  5. Ibid.
  6. Griffiths JC, Edwards J, Fitzpatrick, et al. “Development of a Consensus Approach for Botanical Safety Evaluation.” The Toxicologist. 2018.
  7. Galli CL, Walker NJ, Oberlies NH, Roe AL, Edwards J, Fitzpatrick S, Griffiths JC, Hayes AW, Mahony C, Marsman DS and O’Keeffe L. “Development of a Consensus Approach for Botanical Safety Evaluation – A Roundtable Report.” Toxicology Letters. 2019. https://www.ncbi.nlm.nih.gov/pubmed/31082523. Accessed 17 June 2019.
  8. Statement from FDA Commissioner Scott Gottlieb, MD, on the agency’s new efforts to strengthen regulation of dietary supplements by modernizing and reforming FDA’s oversight. 2019. FDA website. https://www.fda.gov/news-events/press-announcements/statement-fda-commissioner-scott-gottlieb-md-agencys-new-efforts-strengthen-regulation-dietary. Accessed 17 June 2019.
  9. Roe AL, Dever JT, Gafner S, Marsman DS, Rider CV and Swift S. “The Botanical Safety Consortium.” Appl. In Vitro Toxicol. 2019;5(1).
 
About the Authors
 
Daniel S. Marsman, DVM, PhD, is head of product safety for P&G Health Care. In his role at P&G as a veterinary scientist and board-certified toxicologist, he has led global safety and regulatory initiatives for an array of natural health products, medicines and consumer goods. He can be contacted at  marsman.ds@pg.com.
 
Joseph T. Dever, PhD, is a board-certified toxicologist and manager of product safety at Amway Corporation. He oversees a global safety program for all nutrition and cosmetic products including the NutriliteTM and ArtistryTM brands. He can be contacted at Joe.Dever@Amway.com.
 
Stefan Gafner, PhD, is currently chief science officer of the American Botanical Council (ABC), an independent, nonprofit research and education organization. He is also technical director of the ABC-AHP-NCNPR Botanical Adulterants Program, a large-scale collaborative program initiated by the American Botanical Council (ABC), the American Herbal Pharmacopoeia (AHP) and the National Center for Natural Product Research (NCNPR) at the University of Mississippi to educate members of the herbal and dietary supplement industry about ingredient and product adulteration. He can be contacted at stefan@herbalgram.org.
 
Cynthia Rider, PhD, is a toxicologist with the National Toxicology Program (NTP), National Institute of Environmental Health Sciences (NIEHS), where she serves as a project leader for testing programs including botanical dietary supplements. Her research focuses on evaluating and refining methods to predict mixture toxicity based on data from components or whole reference mixtures. She can be contacted at cynthia.rider@nih.gov.
 
Sibyl Swift, PhD, is a special assistant within the US Food and Drug Administration’s (FDA’s) Office of Dietary Supplement Programs (ODSP). In this role, Swift works on special projects related to dietary supplements, including directing the Office’s research agenda and reviewing dietary ingredient safety. She can be contacted at sibylswift@fda.hhs.gov.
 
James C. Griffiths, PhD, is senior vice president of International and Scientific Affairs at the Council for Responsible Nutrition (CRN).  He is a board-certified toxicologist and has been active in product safety, nutrition and international issues throughout a thirty-year scientific career. He can be contacted at  jgriffiths@crnusa.org.
 
Cite as: Marsman, DS, Dever, JT, Gafner, S, Rider, C, Swift, S and Griffiths, JC. “The Botanical Safety Consortium (BSC): The Development of a 21st Century Framework for Assessing the Safety of Botanical Dietary Supplements.” Regulatory Focus. June 2019. Regulatory Affairs Professionals Society.

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