Safety Evaluation and Safety of Sweeteners by Dr. Bernadene

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

Safety Evaluation and Safety of Sweeteners by Dr. Bernadene

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