Safety Evaluation and Safety of Sweeteners

1. Safety Evaluation and Safety of Sweeteners Bernadene Magnuson, Ph.D.

2. Outline • Overview of safety evaluation • Risk assessment paradigm • Safety studies • Overview of safety of sweeteners • Aspartame • Acesulfame K • Sucralose • Stevia extracts • Conclusions

3. Safety Evaluation • Risk assessment paradigm Identify Hazard Characterize Dose-Response Estimate Acceptable Daily Intake (ADI)

4. 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.)

5. 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

6. Identify Hazard Characterize Dose-Response Assess Exposure Estimate Acceptable Daily Intake (ADI) Estimate Range/Distribution of Human Intakes Food survey for target population Risk assessment paradigm Characterize Risk What fraction of the population, if any, incurs intakes greater than the ADI? To what extent do intakes exceed the ADI?

7. 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

8. Number of Servings/Day to Reach ADI

9. Aspartame metabolism Intestinal Lumen Mucosa Cell Portal Blood Aspartame Aspartame Esterases Esterases Methanol Aspartame does not enter blood Methanol (10%) Aspartame Methanol + Asp/Phe Asp/Phe Peptidases Peptidases Aspartate (40%) Aspartate + Aspartate + Phenylalanine (50%) Phenylalanine Phenylalanine Dipeptide Transport System

10. Aspartame controversies • 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

11. 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?

12. 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

13. Acesulfame K • Discovered in 1967 • 200 times sweeter than sucrose • Commonly blended with aspartame • 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

14. Acesulfame K: Metabolism • Rapidly absorbed • Excreted unchanged in the urine within 24 hours in rats, dogs, and humans • No accumulation in the body

15. 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

16. 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 Consumption studies: Australia, Canada, New Zealand, Average users: <3% ADI; Highest users: ~15% ADI No report of highest user exceeding ADI

17. 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

18. 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

19. Stevia extracts Rebaudioside A Stevioside • 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

20. 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 Steviol Backbone

21. 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

22. 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.

23. THANK YOU! QUESTIONS?

24. 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