Consultants in
Human Health,
Toxicology &
Regulatory Affairs
Safety Evaluation and
Safety of
Sweeteners
Bernadene Magnuson, Ph.D.
Outline
• Overview of safety evaluation
– Risk assessment paradigm
– Safety studies
• Overview of safety of sweeteners
– Aspartame
– Acesulfame K
– Sucralose
– Stevia extracts
• Conclusions
Safety Evaluation
• Risk assessment paradigm
Identify Hazard
Characterize Dose-Response
Estimate Acceptable Daily
Intake (ADI)
Premarket Safety Evaluation
• Comprehensive battery of studies are
conducted in multiple species
–
–
–
–
–
–
Acute, sub-chronic, long-term toxicity
Pharmacokinetics, metabolism
Carcinogenicity
Genetic toxicity
Reproductive toxicity, teratogenicity
Human clinical studies
• Data reviewed by food authorities (FDA,
Health Canada, EU, JECFA, etc.)
ADI
• Acceptable Daily Intake (ADI) = amount
considered safe to consume every day for a
life time without adverse effects
• ADI is set by food authorities
– No-Observed Effect Level (NOEL) in chronic studies
– Apply “safety factors” to account for
• differences between individuals (10 X)
• differences between humans and animals (10 X)
• NOEL/100 = ADI (mg/kg/day)
– Consumption greater than ADI still likely to have no
effect because of conservative nature and “safety factor
cushion”
Risk assessment paradigm
Identify Hazard
Characterize Dose-Response
Assess Exposure
Estimate Acceptable Daily
Intake (ADI)
Estimate Range/Distribution
of Human Intakes
Characterize Risk
What fraction of the
population, if any, incurs
intakes greater than the ADI?
To what extent do intakes
exceed the ADI?
Food survey for
target population
Aspartame
• Discovered in 1965
• 200 times sweeter than
sucrose
• Approved in over 130
countries
• ADI: 40 (JECFA); 50 (FDA)
Consumption studies: Australia, Brazil, Canada,
Denmark, France, Germany, Italy, Korea, Netherlands,
New Zealand, Portugal, Spain, Sweden, UK, US.
Average users: <1-10% ADI; Highest users: 45% ADI
No report of even highest user exceeding ADI
Number of Servings/Day to Reach ADI
Food/Beverage
Carbonated soft drink
(12 oz.)
Powdered soft drink (8
oz.)
Gelatin (4 oz.)
Tabletop sweetener
(packet)
Adult
Child
70 kg
16-20
23 kg
5-6
26-33
9-11
34-42
11-14
80100
26-32
Aspartame metabolism
Intestinal Lumen
Mucosa Cell
Aspartame
Aspartame
Esterases
Esterases
Methanol
Aspartame(10%)
Asp/Phe
Peptidases
Aspartate (40%)
+
Phenylalanine (50%)
Methanol
Portal Blood
Methanol
+
Asp/Phe
Peptidases
Aspartate
+
Phenylalanine
Dipeptide Transport
System
Aspartate
Phenylalanine
Aspartame
does not
enter
blood
Aspartame controversies
•
Is aspartame linked to effects on
behavior or the nervous system?
– Many animal studies:
•
Healthy, genetically predisposed, induced disorders
•
Normal children, hyperactive children, children with
PKU, aggressive school boys, sugar-sensitive
children
Healthy adults, airplane pilots, adults with Parkinson’s
disease, adults with depression
– Many human studies
•
• No effect on learning, cognitive
performance, behavior, seizures, or any
other neurological parameter
Does aspartame cause cancer?
• 16 chronic animal studies: multiple species
– 14 found no evidence of carcinogenic or promoting
effects of aspartame
– Only studies reporting positive results by Soffritti et al.
• Detailed review of protocol and data of Soffritti by:
– EFSA, 2006; Agence Franciase de Securite Santarie des
Aliments (2006); US National Toxicology Program; FDA,
Health Canada; Expert panel (Crit Rev Toxicology, 2007)
• All agreed that:
– “there is no credible evidence that
aspartame is carcinogenic”
– “no need to further review the safety of aspartame”
– “no need to revise previously established ADI”
Is aspartame safe for children?
• Metabolism of aspartame
– 1 yr infants and older children;
– No difference between children and adult
• Effect on behavior assessed
– No effect even with habitual use
• Effect on childhood cancers
– No association
Aspartame is safe for children (>1 yr)
at levels consumed
Acesulfame K
• Discovered in 1967
• 200 times sweeter
than sucrose
• Commonly blended
with aspartame
H3C
O
O
S O
N
+
K
O
• JECFA ADI = 15
Consumption studies: Australia, Canada, France,
Netherlands, New Zealand, Spain, Sweden, UK, US
Average users: <10% ADI; Highest users: ~30% ADI
No report of highest user exceeding ADI
Acesulfame K: Metabolism
• Rapidly absorbed
• Excreted unchanged in the urine
within 24 hours in rats, dogs, and
humans
• No accumulation in the body
Acesulfame K: Safety
• Can acesulfame K cause cancer?
– No evidence in preclinical studies with
healthy animals
– No evidence of carcinogenicity in cancerprone mice
• Does acesulfame K increase insulin
secretion?
– No effects observed in in vivo studies
Sucralose
HO
HO
Cl
OH
O
Cl
HO
O
OH
O
Cl
• Discovered in 1976
• 600 times sweeter
than sucrose
• Heat-stable – can be
used in various food
applications
• Approved for use in
over 60 countries
• JECFA ADI = 15
Consumption studies: Australia, Canada, New Zealand,
Average users: <3% ADI; Highest users: ~15% ADI
No report of highest user exceeding ADI
Sucralose: Metabolism
• Approximately 85% of ingested
sucralose is not absorbed and is
eliminated in the faeces unchanged
• Of the absorbed sucralose (15%):
– 2 to 3% glucuronidated and excreted in urine
– Remainder excreted unchanged in urine
• No bioaccumulation.
• Gut microflora unable to hydrolyse
sucralose
Sucralose : SAFETY
• Large body of research
• Preclinical studies have not
demonstrated any toxicities
• Human tolerance studies have
demonstrated no adverse effects at
dosages equivalent to ADI for up to
6 months
Stevia extracts
O
glucose
glucose
O
O
glucose
O
glucose
CH3
O
Rebaudioside A
CH3
CH2
O
glucose
H
CH3
CH2
H
H
O
glucose
glucose
H
CH3
Stevioside
O
O
• Hot-water extracts from the leaves of the Brazilian
shrub Stevia rebaudiana
• Contains many steviol glycosides, with highest
percentage of stevioside and rebaudioside A
• JECFA ADI = 4 mg/kg/day, as steviol equivalents
• Rebaudoside A preparation permitted in U.S. for
food use
Stevia extracts: Metabolism
OR2
CH3
H
R1O
H
CH3
O
Steviol Backbone
CH2
• Glucosides not absorbed
• Steviol glycosides
hydrolysed to steviol by
gut microflora
– Rate depends on number of
glucose moieties attached to
steviol backbone
• Steviol absorbed in large
intestine, glucuronidated
and excreted
– Rats: faeces
– Humans: urine
Stevia extracts: Safety
• Effect on blood glucose homeostasis,
blood pressure, reproduction or kidneys?
– Studies conducted with crude or low-purity extracts
have demonstrated that extracts may have these
effects
– Studies conducted with high-purity extracts (>95%
steviol glycosides) have shown no adverse effects
JECFA confirmed the safety of steviol
glycosides in 2008, changing temporary
ADI to full ADI, based on the new studies
Conclusions
A large body of evidence is required
to support safety, and is critically
reviewed by health authorities.
All approved sweeteners are safe.
No evidence of adverse effects of
non-nutritive sweeteners at levels of
human consumption, by even
highest users.
Consultants in
Human Health,
Toxicology &
Regulatory Affairs
THANK YOU!
QUESTIONS?
Neotame
• Derivative of Aspartame
• 7000x sweeter than sugar
• Metabolized by removal of methyl
group, to desterified neotame
• No adverse effects
• ADI: 2 mg/kg/day, FDA