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Ephedra Risk Assessment

Alyssa Vivas Ashley Barlond ENVH 472. Ephedra Risk Assessment. What is ephedra ?. Herbal remedy derived from plant ( Ephedra sinica ) Chinese herb derivative in dietary supplements Acts as a stimulant Constricts blood vessels

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Ephedra Risk Assessment

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  1. Alyssa Vivas Ashley Barlond ENVH 472 Ephedra Risk Assessment

  2. What is ephedra? • Herbal remedy derived from plant (Ephedrasinica) • Chinese herb derivative in dietary supplements • Acts as a stimulant • Constricts blood vessels • Increases BP, HR, metabolism, body heat, & expands bronchial tubes • Different than ephedrine • Ephedra: plant • Ephedrine: Main active ingredient, similar to amphetamine • Stimulate NS & heart

  3. Common Uses… • Herbal remedy to treat respiratory problems (i.e. asthma, cold/flu symptoms) • Weight loss supplements • Athletic enhancement • Energy supplements • Treatment of Hypotension • Herbal street drug alternative

  4. Background • 1990’s – first entered U.S. market -FDA investigates adverse events • 1994 – DSHEA (Dietary Supplements Health & Education Act) • 1997– FDA proposed ruling for banning: >8mg • - stricter labeling of low-dose ephedra supplements • 2001 – Minnesota Vikings player died (suspected) • 2003 – Studies confirm negative effects, consumer alert • 2003 – Orioles Pitcher Steve Bechler died • 2004 – FDA bans ephedra • Stopped retail sales, manufacture, and distribution • Ephedra considered “adulterated” • Ephedra manufacturers tried to lobby against it • 2005 – Utah judge tried to overturn ban • 2006 – Federal appeals court reaffirms FDA ban & overturns UT judge • After ban: dietary supplement companies replaced ephedra with other herbal stimulants; marketed them as “ephedra-free” • FDA = no dose of ephedrine alkaloids safe!

  5. Risk Assessment • Hazard Identification • Exposure Assessment • Dose-Response Assessment • Risk Characterization

  6. Hazard Identification To gain background, FDA uses data from: • Adverse event information • FDA received 140 adverse event reports from 6/1/97 to 3/31/99 • 22 “attributable • 33 “supportive” • 72 “insufficient data” • 8 “not evaluated” • Clinical studies & scientific reviews • NIH  RAND Corp. evaluated safety & efficacy

  7. Hazard Identification (con’t) Does ephedra really work? • short-term weight loss • increased energy, endurance, and strength BUT There are serious side effects!

  8. Hazard Identification (con’t) • Originally thought of as safe because it’s natural, but serious CV & CNS side effects (even in small doses): • Hypertension • Dizziness • Nervousness • Trembling • Headache • Insomnia • Dehydration • Vomiting • Irregular heartbeat • Seizures • Heart attack • Stroke

  9. Hazard Identification (con’t) • Can cross blood-brain barrier and become potent CNS stimulator • More hazardous when combined with caffeine Synergistic effects • Can ultimately lead to death • Half-life: 3-6 hours • Excreted largely unchanged in urine

  10. Hazard Identification (con’t) • Past study found: • Ephedra use related to stroke, heart attack, sudden death • Don’t need to be pre-disposed to heart problems to have severe side effects • Toxic effects even with low doses • Induces cardiotoxic problems: lesions, hemorrhage, necrosis, and degeneration.

  11. Hazard Identification: Toxicology Proposed Mechanism of Heart Toxicity Ephedrine + Caffeine oral exposure Quick Absorption (toxic levels develop within 1 hr) “Fight-or-flight” hormones released Blood vessels narrow (result in high BP) Increase in heart rate Chest pain; heart not getting enough O2-rich blood Heart cell & tissue death Hemorrhage Sudden Death

  12. Exposure Assessment Route • Ingestion (main method); injections (less common) • Excreted in breastmilk Endpoint • Heart/Cardiovascular system Amount Dietary supplements: Typical pills contain 10-50 mg per pill, x3 doses per day =30-150 mg/day

  13. Exposure Assessment (con’t) Duration • 3 doses/day Who • Athletes (increased energy & stamina) • Others: • Dieters (aids weight loss) • People who use street drugs (herbal alternative to drugs) • People who use it as herbal remedy (respiratory problems) 2003- Pitcher Steve Bechler died after taking ephedra.

  14. Dose-Response Assessment Before FDA ban… NOAEL: 90 mg/day = 1.3 mg/kg*day LOAEL: 150 mg/day = 2.1 mg/kg*day But not enough supporting evidence was found as to how these values were calculated. Given past studies about adverse effects associated with even low doses of ephedra, we think NOAEL & LOAEL are NOT valid.

  15. Dose-Response Assessment (con’t) Animal study: effects of ephedra + caffeine significantly increased cardiotoxicity (hemorrhage, necrosis, ventricle degeneration)

  16. Our Risk Assessment Using numbers from animal study… NOAEL: 15 mg/kg*day = 0.015 mg/kg*day 1000 LOAEL: 30 mg/kg*day = 0.030 mg/kg*day 1000

  17. Intake Calculation based on FDA limits Before, ban FDA recommended 24 mg maximum dose of ephedra per day. Based on this… C (concentration): n/a CR (contact rate): 24 mg/day BW (body weight): 70 kg I (intake): ?? I = C * CR * EFD BW * AT I =(24 mg/day ) 70 kg I = 0.34 mg/kg*day Our NOAEL/LOAEL values are lower!

  18. Risk Characterization • Habit-forming • Can build up tolerance  leads to higher doses for same effect • Based on precautionary assessment, risk is mild

  19. Precautionary Assessment • Not supportive of health or community

  20. Precautionary Assessment • Mild exposure risk

  21. Precautionary Assessment • Medium-high hazard & toxicity

  22. Precautionary Approach

  23. Limitations of Risk Assessment • Lack of adequate data • Animal studies • No strong evidence that ephedra actually enhances athletic performance • Low dose extrapolation • Don’t really know the least dosage when side effects occur • Multiple chemical exposures • Amount of caffeine taken with ephedra varies & could have role in severity of side effects

  24. Risk-Benefit Analysis • Feb 2004, FDA published final ruling that supplements with ephedrine alkaloids present unreasonable risk of illness or injury • Ex 1 : no significant differences in strength, endurance, power when taken as an athletic supplement • Ex 2: Weight loss associated with ephedra is only short-term and not sufficient enough to “cure” obesity. Severe heart and nervous system risks outweigh weight loss • July 2008 Final Rule: “… dietary supplements that contain ephedrine alkaloids are adulterated under section 402(f)(1)(A) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 342(f)(1)(A)). It is illegal to market an adulterated dietary supplement.”

  25. FDA’s Lack of Power • Federal Food and Drug Administration (FDA): • Main Task: Protect public from harmful products • Ephedra considered dietary/herbal supplement • Not a drug  FDA cannot regulate it • FDA doesn’t regulate manufacturer’s potentially false claims

  26. Groups with Economic Interests • “Stakeholders“ • Dietary supplement manufacturers • Ex: Metabolife contributed millions to national politicans to sway their vote in favor of ephedra • Received 14,000+ adverse event reports from ephedra, but not reported to FDA • Can make unproven health claims • Not required to report adverse reactions • Labels don’t list all ingredients, real dosage, adverse effects

  27. Groups Claims/Scientific Uncertainty • “Asia MedLabs” (ephedra manufacturer) • Made medical claims w/o scientific evidence • treats flu, fever, allergies • Manufacturers hired private consulting firm = scientific review claiming ephedra is safe • Manufacturers claimed: • **Decreasing obesity outweighs risks of ephedra • Insufficient evidence to support athletic-enhancing benefits of ephedra

  28. Portrayal by Media • Manufacturers advertisements attract consumers • Media introduced it to public w/ national headlines of Baltimore Orioles death • Death: drew attention & thought to be key factor in FDA’s push • National headlines = FDA warning • Media reinforcing FDA= ephedra dangerous • Stigma of WLS:Fear of WLS

  29. Risk Management • In the hands of manufacturers w/: • Dietary Supplement Health & Education Act (DSHEA) • Before market: Manufacturer evaluates safety of WLS before reaches market • On market: • FDA regulates unsafe WLS products • FTC regulates advertising • **DSHEA makes it harder for FDA to protect public • Barriers to consensus: • WLS manufacturers have strong lobbying against amending DSHEA • Lack of evidence (except ephedra) to prove DSHEA not adequately protecting public

  30. What we think… • FDA: 0.34 mg/kg*day • Ours: 0.015 mg/kg*day • Ban should have happened long time ago • More stringent regulations during pre-manufacturing/ marketing of WLS • Regulate like a drug = need to tell consumers risks • Need to amend DSHEA • Promote healthy way to lose weight other than supplements

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