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 HazardCharacterize 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.)

• 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

Risk assessment paradigm

Identify HazardCharacterize Dose-Response

Assess Exposure

Characterize RiskWhat 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 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

Food/Beverage Adult 70 kg

Child23 kg

Carbonated soft drink (12 oz.)

16-20 5-6

Powdered soft drink (8 oz.)

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

Intestinal Lumen Mucosa Cell

Methanol

Aspartate

Phenylalanine

Aspartame

Portal Blood

Aspartame

Esterases

Methanol (10%)

Asp/Phe

Aspartate (40%)

Phenylalanine (50%)

Peptidases

+

Dipeptide Transport System

Aspartame

Esterases

Methanol

Asp/Phe

Aspartate

Phenylalanine

Peptidases

+

+

Aspartame metabolism

Aspartame does not

enter blood

• Is aspartame linked to effects on behavior 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-sensitive children

• Healthy adults, airplane pilots, adults with Parkinson’s disease, adults with depression

• No effect on learning, cognitive performance, behavior, seizures, or any other neurological parameter

Aspartame controversies

• 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?

• 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 children?

Acesulfame K

• Discovered in 1967

• 200 times sweeter than sucrose

• Commonly blended with aspartame

• JECFA ADI = 15

N

SO

O-

O

OH3C

K+

Consumption studies: Australia, Canada, France, Netherlands, New Zealand, Spain, Sweden, UK, USAverage 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 cancer-prone mice

• Does acesulfame K increase insulin secretion?– No effects observed in in vivo studies

Sucralose• 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

O

O

Cl

HO

OH

HO

O

HO OH

Cl

Cl

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 glucoseO

glucose

glucose

O

glucose

H

H

CH3CH2

O

CH3

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

glucoseO

glucose

O

glucose

H

H

CH3CH2

O

CH3

O

Rebaudioside A

Stevioside

Stevia extracts: Metabolism

• 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

R1O

H

H

CH3CH2

O

CH3

OR2

Steviol Backbone

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