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

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Toxicology of Dietary Supplements National
Capital Area ChapterSociety of Toxicology, Fall
SymposiumNational 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 /
sdentali_at_ahpa.org
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American HerbalProducts Association

• 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.

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American HerbalProducts Association

• 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 _at_ www.ahpa.org

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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.

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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.

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Pyrrolizidine Alkaloids

• Structures from International Programme on
  Chemical Safety, Environmental Health Criteria
  80, Pyrrolizidine Alkaloids, WHO document 1988

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Requirements of Toxicity

• C-1C-2 double bond
• Esterified OH at C-9 and/or C-7
• At least one branched chain in the ester(s)

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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

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Mechanism of Toxicity
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Pyrrolizidine Alkaloids examples

• symphytine

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Pyrrolizidine Alkaloids examples

• monocrotaline

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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.

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AHPAs Position on Pyrrolizidine Alkaloids

• Adopted July 1996
• AHPA recommends that all products with botanical
  ingredients which contain toxic pyrrolizidine
  alkaloids1 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.

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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.

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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.
  86453-60.

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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

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Compounds in skullcap
Baicalein R1 R2 H, R3 OH Wogonin
R1 R3 H, R2 OCH3 Lateriflorein R1 OCH3,
R2 H, R3 OH

• 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.

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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

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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. 141254-8.
• 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).

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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.

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ginkgo and colchicine

• Ginkgolides are trilactone diterpenes w/
  tert-butyl group

• Colchicine is a phenylalanine and tyrosine
  derivative

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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 151174-8.
• 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

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Blue Cohosh - Baby

• Blue cohosh and perinatal stroke. Finkel RS,
  Zarlengo KM. N Engl J Med. 2004 Jul 351302-3.
• 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.

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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.

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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.

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Science by Press Release

• Ocular side effects from herbal medicines and
  nutritional supplements. Fraunfelder FW. Am J
  Ophthalmol. 2004.138639-647.
• 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.

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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.

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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 DSand 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 161805-10.
• Do patients tell their doctor the truth about OTC
  and recreational drug use, diet and exercise,
  smoking?
• There is a doctor patient communication problem.

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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.

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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 229698-704.
• 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.

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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. 75P35.
• 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.

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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.