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Alyssa Vivas
Ashley Barlond
ENVH 472
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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
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Different than ephedrine
 Ephedra: plant
 Ephedrine: Main active ingredient, similar to
amphetamine
 Stimulate NS & heart
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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
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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
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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!
1)
Hazard Identification
2)
Exposure Assessment
3)
Dose-Response Assessment
4)
Risk Characterization
To gain background, FDA uses data from:
 Adverse event information
 FDA received 140 adverse event reports from 6/1/97 to 3/31/99
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22 “attributable
33 “supportive”
72 “insufficient data”
8 “not evaluated”
Clinical studies & scientific reviews
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NIH  RAND Corp. evaluated safety & efficacy
Does ephedra really work?
 short-term weight loss
 increased energy, endurance, and strength
BUT
There are serious side effects!
 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
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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
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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.
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
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
Duration
 3 doses/day
Who
 Athletes (increased energy
& stamina)
 Others:
2003- Pitcher Steve Bechler died
after taking ephedra.
Dieters (aids weight loss)
People who use street drugs (herbal alternative to drugs)
People who use it as herbal remedy (respiratory
problems)
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.
Animal study: effects of ephedra + caffeine significantly
increased cardiotoxicity (hemorrhage, necrosis, ventricle
degeneration)
Uncertainty Factors
Interspecies variability
10
Intraspecies variability
10
Database uncertainty
10
TOTAL
1000
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
Before, ban FDA recommended 24 mg maximum
dose of ephedra per day. Based on this…
I = C * CR * EFD
BW * AT
I =(24 mg/day )
70 kg
I = 0.34 mg/kg*day
C (concentration): n/a
CR (contact rate): 24 mg/day
BW (body weight): 70 kg
I (intake): ??
Our NOAEL/LOAEL values are lower!
 Habit-forming
 Can build up tolerance  leads to higher
doses for same effect
 Based on precautionary assessment, risk is
mild
Initial
G
Parameter
Score
Community / Social Issues
Evaluate effects on the community and related social issues.
G=Goal
3
1-a lot, 2-some, 3-little. Does this move forward the goal of
human and environmental health?
3
1-a lot, 2-some, 3-little or not sure. Ask the question: Is it
necessary? Do we really need this?
1
1-little, 2-some, 3-high impact. Is there a potential impact
on future generations of humans and other species?
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.
2
1-alternatives were carefully considered, 2-some
consideration, 3-no consideration. Were alternatives
considered?
N
N=Need
F
F=Future
Generations
D
D=Democratic,
community based
process
A
Comment
A=Alternatives
Total
12/15
5-good, supportive of health and community
15-poor, not supportive of health or community
Not supportive of health or community
Exposure Issues
Evaluate potential exposure issues.
E
E=Exposure
3
0-none, 1-little, 2-some, 3-high. Do we have control over the
exposure?
M
M=Multiple
exposures
1
0-none, 1-little, 2-some, 3-high. Is there exposure to other chemicals
with similar hazard?
Ch
Ch=Children
exposed
3
0-none, 3-little, 5-some or high or don't know. Children are often
more vulnerable. Are children being exposed.
CP
CP=Consumer
products
2
0-not in consumer products, 1-little, 2-some, 3- a lot or do not know. Is
this compound in consumer products?
O
O=Occupational
exposure
0
0-no occupational exposure, 1-little, 2-some, 3- a lot or do not know. Is
there occupational exposure?
F
F=Food exposure
0
0-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 problems
20-significant exposure, serious concern
Mild exposure risk
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)
IS
IS=Individual
Sensitivity
2
1-little 2-some, 3-a lot. Determine if any individuals are more
sensitive than health adult such as the very young or old.
EC
EC=Ecological
hazard
1
1-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
1
1-little persistence 2-some, 3-a lot of persistence or do not know. Is
the compound presistent in the environment?
B
B=Bioaccumulate
1
1-little 2-some, 3-a lot. Does it bioaccumulative in humans or
animals or move up the food chain?
UC
UC=Uncertainty
2
1-little 2-some, 3-a lot. How certain is the information?
Total
22/30
7-low hazard
30-significant hazards or unknowns, serious concern
Medium-high hazard & toxicity
Final Results
Community/Social Issues
12/15
Exposure Issues
9/20
Hazard/Toxicity
22/30
TOTAL:
43/65
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
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Feb 2004, FDA published final ruling
that supplements with ephedrine
alkaloids present unreasonable risk of
illness or injury
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 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.”
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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
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“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
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“Asia MedLabs” (ephedra
manufacturer)
 Made medical claims w/o
scientific evidence
 treats flu, fever, allergies
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Manufacturers hired private
consulting firm = scientific review
claiming ephedra is safe
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Manufacturers claimed:
 **Decreasing obesity
outweighs risks of ephedra
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Insufficient evidence to
support athletic-enhancing
benefits of ephedra
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Manufacturers advertisements attract
consumers
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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
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Stigma of WLS: Fear of WLS
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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
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Barriers to consensus:
 WLS manufacturers have strong
lobbying against amending DSHEA
 Lack of evidence (except ephedra) to
prove DSHEA not adequately
protecting public
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FDA: 0.34 mg/kg*day
Ours: 0.015 mg/kg*day
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Ban should have happened
long time ago
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More stringent regulations
during pre-manufacturing/
marketing of WLS
 Regulate like a drug = need to
tell consumers risks
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Need to amend DSHEA
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Promote healthy way to lose
weight other than
supplements