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

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


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

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 /
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

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_

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.

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
  • However, Echinacea lacks the 1,2 saturated
    necrine ring associated with hepatoxicity of
    pyrrolizidine alkaloids.

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

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)

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

Mechanism of Toxicity
Pyrrolizidine Alkaloids examples
  • symphytine

Pyrrolizidine Alkaloids examples
  • monocrotaline

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.

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
  • Borage seed oil is specifically exempt from the
    above label recommendation.

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.

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.

Teucrin A in germander
  • Mechanism known
  • CYP3A oxidation creates reactive electrophilic
  • Probably epoxide
  • Implicated in several human poisonings
  • Structure from European Commission, Scientific
    Committee on Food

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
  • Some members may be of less or no concern.

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

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).

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.

ginkgo and colchicine
  • Ginkgolides are trilactone diterpenes w/
    tert-butyl group
  • Colchicine is a phenylalanine and tyrosine

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
  • (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

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.

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.

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.

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.

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.

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,
  • There is a doctor patient communication problem.

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.

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.

  • Bitter orange juice research is cited, which is
    not relevant to extracts used in dietary
  • A study of 12 human volunteers taking a
    supplement containing bitter orange found no
    effect on drug metabolism and no
  • 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.

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
  • AHPA submitted a Citizen Petition to FDA on March
    20, 2003 to request establishment of a dietary
    supplement AER system.
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