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Toxicology of Dietary Supplements National Capital Area Chapter Society of Toxicology, Fall Symposium National Library of Medicine Bethesda, MD – November.

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Presentation on theme: "Toxicology of Dietary Supplements National Capital Area Chapter Society of Toxicology, Fall Symposium National Library of Medicine Bethesda, MD – November."— Presentation transcript:

1 Toxicology of Dietary Supplements National Capital Area Chapter Society of Toxicology, Fall Symposium National Library of Medicine Bethesda, MD – November 2, 2004 The Industry Perspective Steven Dentali, Ph.D. VP, Scientific and Technical Affairs American Herbal Products Association 301.588.1171 x 103 /

2 American Herbal Products Association2 The National Trade Association and Voice of the Herbal Products Industry The American Herbal Products Association exists to serve its members by promoting the responsible commerce of products which contain herbs and which are used to enhance health and quality of life.

3 American Herbal Products Association3 Founded in 1983 AHPA represents the manufacturers, growers, suppliers and retailers of herbal supplement products. AHPA published Herbs of Commerce and wrote the Botanical Safety Handbook. HerbMed® searchable database on the website @

4 American Herbal Products Association4 DS Toxicology by Science ? Apparent academic bias emerges from ignorance of basic botanical science issues. Proper ID, known phytochemistry, bioactivty of specific chemicals need to be considered. Toxicological issues exist for some dietary supplements and require appropriate attention. Six published reports will be examined.

5 American Herbal Products Association5 Echinacea Hepatotoxicity? Herbal medicinals: selected clinical considerations focusing on known or potential drug-herb interactions. Miller LG. Arch Intern Med. 1998. 158(20):2200-11. If used beyond 8 weeks, Echinacea could cause hepatotoxicity … However, Echinacea lacks the 1,2 saturated necrine ring associated with hepatoxicity of pyrrolizidine alkaloids.

6 American Herbal Products Association6 Pyrrolizidine Alkaloids Structures from International Programme on Chemical Safety, Environmental Health Criteria 80, Pyrrolizidine Alkaloids, WHO document 1988

7 American Herbal Products Association7 Requirements of Toxicity C-1:C-2 double bond Esterified –OH at C-9 and/or C-7 At least one branched chain in the ester(s)

8 American Herbal Products Association8 Toxic Pyrrolic Intermediate Metabolism by MFOs creates pyrrolic dehydro derivatives – alkylating agents Structures from International Programme on Chemical Safety, Environmental Health Criteria 80, Pyrrolizidine Alkaloids, WHO document 1988

9 American Herbal Products Association9 Mechanism of Toxicity

10 American Herbal Products Association10 Pyrrolizidine Alkaloids examples symphytine

11 American Herbal Products Association11 Pyrrolizidine Alkaloids examples monocrotaline

12 American Herbal Products Association12 Pyrrolizidine Alkaloids of echinacea (E. angustifolia, E. purpurea) 1-2 saturation, no branched chain esters Reported in trace amounts (~0.006%) NAS lists pyrrolizidine alkaloids as particularly hazardous without a footnote. Text states some members may be of no concern.

13 American Herbal Products Association13 AHPAs Position on Pyrrolizidine Alkaloids Adopted July 1996 AHPA recommends that all products with botanical ingredients which contain toxic pyrrolizidine alkaloids 1 bear the following cautionary statement on the label: For external use only. Do not apply to broken or abraded skin. Do not use when nursing. 1) Including but not limited to: Alkanna tinctoria (alkanet); Anchusa officinalis (bugloss); Borago officinalis* (borage); Crotalaria spp., Cynoglossum spp., Erechtites hieraciifolia, Eupatorium cannabinum (hemp agrimony); Eupatorium purpureum (Joe Pye), Heliotropium spp., Lithospermum officinale (European gromwell); Packera candidissima, Petasites spp. (e.g., Butterbur); Pulmonaria spp. (e.g., lungwort); Senecio jacobaea (European ragwort); Senecio vulgaris (groundsel herb); Symphytum spp. (comfrey); and Tussilago farfara (coltsfoot). * Borage seed oil is specifically exempt from the above label recommendation.

14 American Herbal Products Association14 Scullcap (sic) likely hazardous May 2004 Consumer Reports article listing Scutellaria lateriflora L. (skullcap) –Based on AERs or theoretical risks Germander (Teucrium chamaedrys L.) listed as very likely hazardous –Liver damage, deaths reported There is a connection here.

15 American Herbal Products Association15 Skullcap and germander Germander has adulterated skullcap and has been implicated as hepatotoxic. Properly identified skullcap has never been implicated as a hazardous herbal ingredient in any product. Reliable methods exist for proper determination of skullcap identity (authentication). Analysis of Scutellaria lateriflora and its adulterants Teucrium canadense and Teucrium chamaedrys by LC-UV/MS, TLC, and digital photomicroscopy. Gafner et al. J AOAC Int. 2003. 86:453-60.

16 American Herbal Products Association16 Teucrin A in germander Mechanism known CYP3A oxidation creates reactive electrophilic furan –Probably epoxide Implicated in several human poisonings Structure from European Commission, Scientific Committee on Food

17 American Herbal Products Association17 Compounds in skullcap Flavones and their glycosides Neoclerodane diterpenes have been isolated but lack a furan moiety. No credible support can be found for listing skullcap as a likely hazardous material. NAS lists diterpene acids as a general class of constituent of concern (grindelic, carnosic acids?) Some members may be of less or no concern. Baicalein R1 = R2 = H, R3 = OH Wogonin R1 = R3 = H, R2 = OCH3 Lateriflorein R1 = OCH3, R2 = H, R3 = OH

18 American Herbal Products Association18 AHPAs Position on Skullcap Adulteration Adopted July 1997 AHPA recommends that appropriate steps be taken to assure that the following raw materials are free of the noted adulterant: Herb in Commerce 1. Eleuthero root (Eleutherococcus senticosus) 2. Plantain leaf (Plantago lanceolata) 3. Skullcap herb (Scutellaria lateriflora) 4. Stephania root (Stephania tetrandra) Adulterant 1. Periploca sepium root 2. Digitalis lanata leaf 3. Germander herb (Teucrium chamaedrys) 4. Aristolochia fangchi root

19 American Herbal Products Association19 Ginkgo, echinacea and colchicine: the report Identification of colchicine in placental blood from patients using herbal medicines. Petty HR et al. Chem Res Toxicol. 2001. 14:1254-8. While characterizing natural antiinflammatory substances in human placental blood, we discovered … the well-known alkaloid, colchicine. (S)ignificant levels … could be found in placental blood of patients using nonprescription herbal dietary supplements during pregnancy. We confirmed the presence of colchicine in commercially available ginkgo (and echinacea).

20 American Herbal Products Association20 Ginkgo, echinacea and colchicine: questions Amount found in placental blood… Limited familial distribution of colchicine –Liliaceae, not Ginkgoaceae or Asteraceae Possible adulteration? Commerical products not identified. Authors not forthcoming with info. Various testing programs ensued.

21 American Herbal Products Association21 ginkgo and colchicine Ginkgolides are trilactone diterpenes w/ tert-butyl group Colchicine is a phenylalanine and tyrosine derivative

22 American Herbal Products Association22 Ginkgo, echinacea and colchicine: responses Evaluation of commercial ginkgo and echinacea dietary supplements for colchicine using liquid chromatography-tandem mass spectrometry. Li W, Sun Y, Fitzloff JF, van Breemen RB. Chem Res Toxicol. 2002 15:1174-8. LC-MS-MS 10 pg detection, 26 samples –Assay was nore selective and sensitive, none positive –(W)e find no cause for concern regarding colchicine contamination of ginkgo or echinacea dietary supplements. Industry ginkgo testing programs –No colchicine detected in bulk materials or finished products

23 American Herbal Products Association23 Blue Cohosh - Baby Blue cohosh and perinatal stroke. Finkel RS, Zarlengo KM. N Engl J Med. 2004 Jul 351:302-3. 24-yr old advised by obstetrician to drink a tea made from blue cohosh (Caulophyllum thalictroides) at 40 wks. She delivered. Infant suffered a stroke a day later. Urine and meconium were positive for the cocaine metabolite benzoylecgonine on screening by immunoassay, and results were confirmed by GC- MS. Testing of the mothers bottle of blue cohosh and contents of a sealed bottle of a different preparation of the herb gave the same results.

24 American Herbal Products Association24 Blue Cohosh Case Questions Is benzoylecgonine a constituent or metabolite of both cocaine and blue cohosh? Was the blue cohosh product contaminated with cocaine and benzoylecgonine? Was mom using cocaine? Can methylcytisine produce a false positive? Was the laboratory in error? What about the safety of blue cohosh? Case reported to FDA ten years ago.

25 American Herbal Products Association25 Blue Cohosh Determinations The findings of cocaine metabolites in different blue cohosh products are inconsistent with its known chemistry and tend to rule out single product adulteration. Other possible explanations, including erroneous analysis and the mother's medical history, should be examined. Original lab records not available. Current analysis of blue cohosh samples negative. Although the reported incidence of adverse events from blue cohosh has been rare its use should only be undertaken with awareness of its potential toxicity.

26 American Herbal Products Association26 Science by Press Release Ocular side effects from herbal medicines and nutritional supplements. Fraunfelder FW. Am J Ophthalmol. 2004.138:639-647. retrospective observational case series of reports of ocular … or systemic side effects Chamomile, datura, Echinacea purpurea, ginkgo, and licorice mentioned. Clinicians need to recognize these adverse events, because a large segment of the population uses them, many times without the treating physician's knowledge.

27 American Herbal Products Association27 Brief analysis of eye problems Chamomile tea used as an eye wash –Nonsterile solution in the eye? Echinacea irritations from topical use –Supplements dont include topical use Datura, questionable use, not a DS –Contains anticholinergic tropane alkaloids hyoscyamine, scopolamine, atropine Temporary vision loss from licorice? Ginkgos blood thinning effects known.

28 American Herbal Products Association28 One big assumption "Most consumers assume because a product is naturally occurring it is safe" As a result, about forty percent of people who use alternative therapies do not discuss them with their doctors. Where is this belief substantiated? In fact… About half of regular users believed that physicians are prejudiced against DS…and that their own physician knows little or not much about these products. –Americans' views on the use and regulation of dietary supplements. Blendon et al. Arch Intern Med. 2001 161:805-10. Do patients tell their doctor the truth about OTC and recreational drug use, diet and exercise, smoking? There is a doctor patient communication problem.

29 American Herbal Products Association29 AHPAs Position on Doctor Notification Tell your doctor that you are using herbs. Insist that they receive this information respectfully and dont be surprised if they are not well informed on the subject. They have a responsibility to safely oversee your use of any prescription drugs. If your doctor is concerned that a pharmaceutical might interact with an herbal product, it is prudent to accept such advice.

30 American Herbal Products Association30 Recent Bitter Orange Review Citrus aurantium, an ingredient of dietary supplements marketed for weight loss: current status of clinical and basic research. Fugh-Berman A, Myers A. Exp Biol Med (Maywood). 2004 229:698-704. C. aurantium contains 6',7'-dihydroxybergamottin and bergapten, both of which inhibit cytochrome P450-3A, and would be expected to increase serum levels of many drugs. Although C. aurantium extract has not been tested in clinical studies, synephrine clearly raises blood pressure in humans and other species.

31 American Herbal Products Association31 However … Bitter orange juice research is cited, which is not relevant to extracts used in dietary supplements. –A study of 12 human volunteers taking a supplement containing bitter orange found no effect on drug metabolism and no 6,7-dihydroxybergamottin. –Assessment of Botanical Supplementation on Human Cytochrome P450 Phenotype: Citrus aurantium, Echinacea, Milk Thistle, Saw Palmetto. Gurley et al. Clin Pharmacol Ther 2004. 75:P35. The evidence for synephrines hemodynamic changes was continuous intravenous administration at 4 mg/minute. This is not directly applicable to oral consumption of bitter orange extracts. The human clinical research cited showed no increase in blood pressure for people taking bitter orange products.

32 American Herbal Products Association32 AHPAs Position on Serious Adverse Event Reporting AHPA believes that manufacturers, packers, and distributors should be required to establish and maintain records and make reports to FDA of all serious adverse dietary supplement experiences that are associated with the use of their products. AHPA submitted a Citizen Petition to FDA on March 20, 2003 to request establishment of a dietary supplement AER system.

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