Ephedra Risk Assessment

Alyssa VivasAshley BarlondENVH 472

What is ephedra?

Herbal remedy derived from plant (Ephedra sinica)

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

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

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!

Risk Assessment

1) Hazard Identification

2) Exposure Assessment

3) Dose-Response Assessment

4) Risk Characterization

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

Hazard Identification (con’t)

Does ephedra really work?short-term weight lossincreased energy, endurance, and

strength

BUT There are serious side effects!

Hazard Identification (con’t)

Originally thought of as safe because it’s natural,but serious CV & CNS side effects (even in small doses):

HypertensionDizzinessNervousnessTremblingHeadache Insomnia

DehydrationVomitingIrregular heartbeatSeizuresHeart attackStroke

Hazard Identification (con’t)

Can cross blood-brain barrier and become potent CNS stimulator

More hazardous when combined with caffeineSynergistic effects

Can ultimately lead to death

Half-life: 3-6 hours Excreted largely unchanged in urine

Hazard Identification (con’t)

Past study found:Ephedra use related to stroke, heart

attack, sudden deathDon’t need to be pre-disposed to heart

problems to have severe side effectsToxic effects even with low dosesInduces cardiotoxic problems: lesions,

hemorrhage, necrosis, and degeneration.

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

Exposure Assessment

RouteIngestion (main method); injections (less common)

Excreted in breastmilk

EndpointHeart/Cardiovascular system

Amount Dietary supplements:Typical pills contain 10-50 mg per pill, x3

doses per day =30-150 mg/day

Exposure Assessment (con’t)

Duration3 doses/day

WhoAthletes (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.

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.

Dose-Response Assessment (con’t)

Animal study: effects of ephedra + caffeine significantly increased cardiotoxicity (hemorrhage, necrosis, ventricle degeneration)

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

Uncertainty Factors

Interspecies variability

10

Intraspecies variability

10

Database uncertainty 10

TOTAL 1000

Intake Calculation based on FDA limits

I = C * CR * EFD BW * ATI =(24 mg/day ) 70 kgI = 0.34 mg/kg*day

C (concentration): n/aCR (contact rate): 24 mg/dayBW (body weight): 70 kgI (intake): ??

Before, ban FDA recommended 24 mg maximum dose of ephedra per day. Based on this…

Our NOAEL/LOAEL values are lower!

Risk Characterization

Habit-forming

Can build up tolerance leads to higher doses for same effect

Based on precautionary assessment, risk is mild

Precautionary Assessment

Initial Parameter Score Comment

 Community / Social Issues

Evaluate effects on the community and related social issues.

G G=Goal 3

1-a lot, 2-some, 3-little. Does this move forward the goal of human and environmental health?

N N=Need 3

1-a lot, 2-some, 3-little or not sure. Ask the question: Is it necessary? Do we really need this?

FF=Future Generations 1

1-little, 2-some, 3-high impact. Is there a potential impact on future generations of humans and other species?

D

D=Democratic, community based process 3

1-a lot of community involvement and consultation, 2-some, 3-little. Was the community consulted early and often in the process? Was the process democratic and inclusive.

A A=Alternatives 2

1-alternatives were carefully considered, 2-some consideration, 3-no consideration. Were alternatives considered?

 Total 12/15 5-good, supportive of health and community

15-poor, not supportive of health or community

Not supportive of health or community

Precautionary Assessment

 Exposure Issues   Evaluate potential exposure issues.

E E=Exposure 30-none, 1-little, 2-some, 3-high. Do we have control over the exposure?

MM=Multiple exposures

10-none, 1-little, 2-some, 3-high. Is there exposure to other chemicals with similar hazard?

ChCh=Children exposed

30-none, 3-little, 5-some or high or don't know. Children are often more vulnerable. Are children being exposed.

CPCP=Consumer products

20-not in consumer products, 1-little, 2-some, 3- a lot or do not know. Is this compound in consumer products?

OO=Occupational exposure

00-no occupational exposure, 1-little, 2-some, 3- a lot or do not know. Is there occupational exposure?

FF=Food exposure

00-not in food supply, 1-little, 2-some, 3- a lot or do not know. Is the compound present in the food supply.

  Total 9/20 0-no exposure, no problems20-significant exposure, serious concern

Mild exposure risk

Precautionary Assessment

  Hazard / Toxicity Evaluate potential hazards.

H H=Hazard 10

1-low, 5-some, 10-high. Follow classical hazard evaluation, pick endpoint, exam relevant quality studies (cancer, reproductive, neurotoxicity, irreversible)

ISIS=Individual Sensitivity

21-little 2-some, 3-a lot. Determine if any individuals are more sensitive than health adult such as the very young or old.

ECEC=Ecological hazard

11-little 2-some, 3-a lot. Is it a hazard to other species or the environment?

V V=Volume 5 how much is produced (1=research only, 2=<1000 lbs, 3=<10,000, 4=<100,000, 5=>100,000 or do not know)

P P=Persistent 11-little persistence 2-some, 3-a lot of persistence or do not know. Is the compound presistent in the environment?

BB=Bioaccumulate

11-little 2-some, 3-a lot. Does it bioaccumulative in humans or animals or move up the food chain?

UCUC=Uncertainty

21-little 2-some, 3-a lot. How certain is the information?

 Total

22/30

7-low hazard30-significant hazards or unknowns, serious concern

Medium-high hazard & toxicity

Precautionary Approach

Final Results

Community/Social Issues 12/15

Exposure Issues 9/20

Hazard/Toxicity 22/30

TOTAL: 43/65

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

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.”

FDA’s Lack of Power

Federal Food and Drug Administration (FDA): Main Task: Protect public from harmful

products

Ephedra considered dietary/herbal supplementNot a drug FDA cannot

regulate itFDA doesn’t regulate

manufacturer’s potentially false claims

Groups with Economic Interests

“Stakeholders“Dietary supplement manufacturers

Ex: Metabolife contributed millions to national politicans to sway their vote in favor of ephedraReceived 14,000+ adverse event reports from ephedra, but

not reported to FDA

Can make unproven health claimsNot required to report adverse reactions

Labels don’t list all ingredients, real dosage, adverse effects

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

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

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 productsFTC 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

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