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Dietary Supplements: A Framework for Evaluating Safety Appendix I Shark Cartilage: Prototype Monograph Summary1 V. SUMMARY AND CONCLUSIONS A. Summary Shark cartilage is not a defined single product. Native shark cartilage is harvested as the tough elastic cartilage, or endoskeleton, of multiple species of shark and contains proteins, proteoglycans, glycosaminoglycans, minerals, carbohydrate, and lipid. Because of harvest conditions, preparations are often contaminated by other shark tissues (e.g., shark liver containing squalamine) and possibly by heavy metals (e.g., mercury) and bacterial and viral contaminants acquired during storage and/or processing. 1 This is a summary of a prototype monograph prepared for the purpose of illustrating how a safety review of a dietary supplement ingredient might be prepared following the format described in this report. While it was prepared as a prototype using the processes described in the report, it was not conducted under the auspices of the Food and Drug Administration utilizing all the resources available to the agency. Thus some pertinent information not available to the Committee could be of importance in evaluating safety to determine if use of this dietary supplement ingredient would present an unreasonable risk of illness or injury. Also, the development and review of this prototype was conducted by individuals whose backgrounds are in general aspects of evaluating science and whose expertise is not necessarily focused specifically on this dietary ingredient, although significant additional assistance was provided by consultants with relevant expertise. Therefore, this prototype monograph, while extensive, does not represent an authoritative statement regarding the safety of this dietary supplement ingredient. The full prototype monograph and its data tables on shark cartilage may be accessed at http://www.iom.edu/fnb.
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Dietary Supplements: A Framework for Evaluating Safety Several very different products are marketed as “shark cartilage,” including aqueous extracts of the homogenized cartilage, and the processing of powdered shark cartilage preparations may include extensive washing, soaking, and/or bleaching. These processes may deplete the product of any readily water-extractable components. While one aqueous extract and a powdered shark cartilage preparation are presently being used in clinical trials to investigate its antitumor potential, information about the composition of this or any other product is not currently available in the public domain. In the absence of information about the specific composition of a shark cartilage product, it must be assumed that adverse effects seen in one product apply to all products labeled as shark cartilage. Human data: Shark cartilage dietary supplements are taken for a variety of conditions. Case reports occasionally mention nonserious side effects such as nausea, vomiting, diarrhea, constipation, and flatulence, but it is unclear whether such effects are due to the supplement, palatability issues, or placebo effects. Serious adverse effects, such as hepatotoxicity, have been anecdotally reported, but specific susceptibility, confounding causes, or other contributing factors were not adequately assessed in the reports. Serious adverse effects have not been observed in clinical trials of specific shark cartilage preparations, but most of these studies are in progress. The studies published to date have not been randomized, double-blind, placebo-controlled trials. Animal data: Animal toxicity studies have been conducted using various types and amounts of shark cartilage preparations and using various routes of administration and laboratory animal species. Details of these studies are not published or available to assess the adequacy of animal toxicity; however, information from summaries and abstracts of nonpublished data do not indicate overt toxicity. In vitro data: Shark cartilage extracts have been shown to inhibit angiogenesis in cell culture experiments. Extracts specifically inhibit the proliferation of endothelial cells in culture media and inhibit the activities of vascular endothelial growth factor and basic fibroblast growth factor in accepted assays for angiogenesis. In vitro studies and other data also demonstrate that shark cartilage powder and extracts possess matrix metalloprotease inhibitors; inhibition of metalloproteinases inhibits angiogenesis. Antiangiogenesis activity of shark cartilage has been confirmed in chick embryonic chorioallantoic membrane (CAM), an accepted assay for angiogenesis. There are no published studies demonstrating antiangiogenic activity in whole animals using shark cartilage via the oral route.
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Dietary Supplements: A Framework for Evaluating Safety Related substances: Related dietary supplements include bovine cartilage, chondroitin sulfate, and glucosamine. The safety of these substances was not thoroughly reviewed for this prototype monograph. Since antiangiogenic activity has been suggested as the mechanism of action of shark cartilage preparations and in vitro studies have shown antiangiogenic potential, it is relevant to consider safety cautions in place for other compounds with antiangiogenic activity (i.e., functional relatedness as described in Chapter 6). Indeed, there is a potential for adverse side effects when angiogenesis is inhibited. For example, thalidomide, a known teratogen, has antiangiogenic activity. Clinical trials using other antiangiogenic agents have reported a wide variety of adverse effects, including neurotoxic effects. Other information: Squalamine, a potential contaminant during processing, has been associated with reversible nonserious side effects (when administered by intravenous infusion to subjects with advanced-stage cancer). B. Conclusions and Recommendations About the Safety of the Ingredient Based on the Strength of the Scientific Evidence There is a substantial lack of safety data for shark cartilage both clinically and in animal toxicity studies, including a lack of any serious adverse event reports. In the context of the large numbers of individuals that have been exposed, the lack of serious acute adverse event reports may be indicative of no serious overt acute toxicity. However, chronic toxicity has not been systematically evaluated. Shark cartilage does not appear to be associated with any serious adverse events, even when taken chronically in gram quantities; however, nonserious side effects have been reported. Nonserious side effects, especially nausea and vomiting, may motivate the individual to discontinue consumption. It should be noted that most clinical trials involved critically ill individuals and thus these gastrointestinal disturbances may be associated with other clinical circumstances or treatments. The incidence of these nonserious side effects is in the range of side effects expected in a placebo group. Although the available evidence does not indicate sufficient evidence for concern about shark cartilage as a dietary supplement ingredient, there has not been a systematic and scientific safety evaluation of shark cartilage. Antiangiogenesis: There is a body of evidence that some shark cartilage preparations, when tested in vitro, contain a substance that has antiangiogenic properties. A common assay used to demonstrate angiogenicity (i.e.,
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Dietary Supplements: A Framework for Evaluating Safety chick embryonic CAM assay) has also been used to determine antiangiogenic activity with shark cartilage preparations. Since thalidomide, a known teratogenic agent, has antiangiogenic effects as one of its mechanisms, it is reasonable to have concerns that the long-term use of shark cartilage preparations could produce teratogenic effects. Antiangiogenic effects might contribute to abnormal fetal development and other physiological conditions (i.e., delayed tissue repair) in which angiogenesis is crucial to the formation of normal structures. Neurotoxicity: Clinical trials are under way based on the presumption that shark cartilage has antiangiogenic activity in vivo. Based on limited animal and in vitro studies, there is no evidence to suggest neurotoxicity. Antiangiogenic agents, based on limited animal and in vitro studies, show no evidence that suggests neurologic toxicity. However, both peripheral and central nervous system toxicity have been reported in a review of short-term clinical studies. Adverse effects included central and peripheral neuropathies (e.g., sustained paralysis, cerebellar ataxia, spastic diplegia, sensory neuropathy, sedation, headache), with some toxicities resolving upon discontinuation of the antiangiogenic agent. These clinical observations support a potential association between shark cartilage preparations with purported antiangiogenic activity and adverse neurological effects. It should be recognized that the subjects in the shark cartilage clinical trials had advanced cancer, other chronic disease, and/or were taking concurrent medications. Many angiogenic mediators can act as neurotrophic factors, and this bioactivity may contribute to neurological abnormalities. Additional studies are warranted to establish the neurotoxic risk from antiangiogenic agents. C. Unresolved Issues and Uncertainties in the Available Data It is very difficult to address the safety of this substance because of the lack of its characterization. There is no generally accepted standard composition of shark cartilage supplements. There are several different products labeled as shark cartilage, and composition differs among them. It is not known if composition changes by batch as well as by product, thereby potentially influencing safety. No active ingredient of shark cartilage preparations has been defined. Furthermore, the effect of processing during the preparation of different products on the bioactivity/bioavailability of the components of shark cartilage is unknown. At this time it cannot be determined whether any of the potential safety issues are relevant to specific shark cartilage preparations or to shark cartilage in general.
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Dietary Supplements: A Framework for Evaluating Safety D. Data Gaps and Future Research Recommended Although the available evidence does not indicate sufficient evidence for concern about shark cartilage as a dietary supplement ingredient, there has not been a systematic and scientific safety evaluation of it. Clinical trials are under way with various preparations of shark cartilage, including clinical trials supported by the National Cancer Institute. These will provide data relevant to safety, and may provide insight into potential serious adverse effects. It is expected that more data will be generated within the next few years as the studies in progress unfold. Other research needed: Characterization of shark cartilage products, including the identification and characterization of bioactive components. Analytical methods (chemical or bioactive assays) for standardization of products. Demonstration and quantification of bioavailability. Acute and chronic animal toxicological data that use currently accepted standards. Ongoing clinical trials that monitor side effects, evaluate safety concerns, and are designed to identify antiangiogenic activity associated with shark cartilage preparations.
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