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8/10/2019 Safety Evaluation and Safety of Sweeteners by Dr. Bernadene
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Consultants in
Human Health,
Toxicology &
Regulatory Affairs
Safety Evaluation and
Safety ofSweeteners
Bernadene Magnuson, Ph.D.
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Outline
Overview of safety evaluation Risk assessment paradigm
Safety studies
Overview of safety of sweetenersAspartame
Acesulfame K
Sucralose Stevia extracts
Conclusions
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Safety Evaluation
Risk assessment paradigm
Identify Hazard
Characterize Dose-Response
Estimate Acceptable Daily
Intake (ADI)
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Premarket Safety Evaluation
Comprehensive battery of studies areconducted 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.)
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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
ADI
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Risk assessment paradigm
Identify HazardCharacterize Dose-Response
Assess Exposure
Characterize Risk
What fraction of the
population, if any, incurs
intakes greater than the ADI?
To what extent do intakes
exceed the ADI?
Estimate Acceptable Daily
Intake (ADI)
Estimate Range/Distribution
of Human Intakes
Food survey fortarget population
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Aspartame
Discovered in 1965
200 times sweeter thansucrose
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:
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Food/Beverage Adult70 kg
Child23 kg
Carbonated soft drink(12 oz.)
16-20 5-6
Powdered soft drink (8oz.)
26-33 9-11
Gelatin (4 oz.) 34-42 11-14
Tabletop sweetener(packet)
80-100
26-32
Number of Servings/Day to Reach ADI
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Intestinal Lumen Mucosa Cell
Methanol
Aspartate
Phenylalanine
Aspartame
Portal BloodAspartame
Esterases
Methanol (10%)
Asp/Phe
Aspartate (40%)
Phenylalanine (50%)
Peptidases
+
Dipeptide TransportSystem
Aspartame
Esterases
Methanol
Asp/Phe
Aspartate
Phenylalanine
Peptidases
+
+
Aspartame metabolism
Aspartame
does notenter
blood
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Is aspartame linked to effects onbehavior or the nervous system? Many animal studies:
Healthy, genetically predisposed, induced disorders
Many human studies Normal children, hyperactive children, children with
PKU, aggressive school boys, sugar-sensitivechildren
Healthy adults, airplane pilots, adults with Parkinsonsdisease, adults with depression
No effecton learning, cognitiveperformance, behavior, seizures, or anyother neurological parameter
Aspartame controversies
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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
Does aspartame cause cancer?
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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
Is aspartame safe for ch i ldren?
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Acesulfame K
Discovered in 1967
200 times sweeter
than sucrose
Commonly blendedwith aspartame
JECFA ADI = 15
N
SO
O-
O
OH3C
K+
Consumption studies:Australia, Canada, France,Netherlands, New Zealand, Spain, Sweden, UK, USAverage users:
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Acesulfame K: Safety
Can acesul fame K cause cancer?
No evidence in preclinical studies withhealthy animals
No evidence of carcinogenicity in cancer-prone mice
Does acesul fame K increase insul in
secret ion? No effects observed in in vivostudies
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Sucralose Discovered in 1976
600 times sweeterthan sucrose
Heat-stablecan beused in various food
applications Approved for use in
over 60 countries
JECFA ADI = 15
O
O
Cl
HO
OH
HO
O
HO OH
Cl
Cl
Consumption studies:Australia, Canada, New Zealand,Average users:
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Sucralose: Metabolism
Approximately 85% of ingestedsucralose 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
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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 to6 months
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Stevia extracts
O glucoseO
glucose
glucose
O
glucose
H
H
CH3CH2
O
CH3
O
Hot-water extracts from the leaves of the Brazilianshrub Stevia rebaud iana
Contains many steviol glycosides, with highestpercentage of stevioside and rebaudioside A
JECFA ADI = 4 mg/kg/day, as steviol equivalents
Rebaudoside A preparation permitted in U.S. for
food use
glucoseO
glucose
O
glucose
H
H
CH3CH2
O
CH3
O
Rebaudioside A
Stevioside
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Stevia extracts: Metabolism
Glucosides not absorbed Steviol glycosides
hydrolysed to steviol by
gut microflora
Rate depends on number ofglucose moieties attached to
steviol backbone
Steviol absorbed in large
intestine, glucuronidatedand excreted Rats: faeces
Humans: urine
R1O
H
H
CH3CH2
O
CH3
OR2
Steviol Backbone
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Conclusions
A large body of evidence is requiredto 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 ofhuman consumption, by even
highest users.
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Consultants in
Human Health,
Toxicology &
Regulatory Affairs
THANK YOU!
QUESTIONS?
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Neotame
Derivative of Aspartame
7000x sweeter than sugar
Metabolized by removal of methylgroup, to desterified neotame
No adverse effects
ADI: 2 mg/kg/day, FDA