1. Aspartame Risk Assessment Food Safety Analysis Exercise Charles Yoe, Ph.D. College of Notre Dame of Maryland

2. Food Additives Chemicals added to food in small amounts –Direct additives –Indirect additives

3. Direct Additives Deliberately added Make food look and taste better Maintain or improve nutritive value Maintain freshness Help processing or preparation Help preserve food Intense sweeteners

4. Indirect Additives Enter food incidentally during –Handling –Processing (equipment) –Packaging

5. Is aspartame safe?

6. Risk Analysis Risk Assessment Risk Management Risk Communication

7. Why Do Risk Analysis? To improve decisions To help assure a safe domestic food supply Its essential for international trade To enable industry to innovate Because we have to

8. Risk Assessment What can go wrong? How can it happen? How likely is it? What are the consequences?

9. Risk Management What question(s) do we want risk assessment to answer? What can be done to reduce the impact of the risk described? What can be done to reduce the likelihood of the risk described? What are the trade-offs of the available options? What is the best way to address the described risk?

10. Risk Communication With whom do you communicate? How do you get both the information you need and the information others have? How do you convey the information you want to communicate? When do you communicate?

11. Food Additive Safety Analysis Amount of substance consumed Safe amount of substance >1 => not safe = 1 => safe safe

12. Food Safety Assessment Not True Risk Assessment Food safety assessment procedures are widely accepted globally They do not assess the risks of an additive They identify a level considered safe for the population Risks are managed rather than explicitly assessed

13. Does It Answer the Questions? What can go wrong? Cancer How can it happen? Uncertain mechanism How likely is it? Unknown What are consequences? Possible death

14. It Does Answer What can be done to reduce the impact of the risk? –Limit intake What can be done to reduce the likelihood of the risk? –Limit intake Food safety assessment is risk management not risk assessment

15. What Do We Know About Aspartame? Why do we care about it? How do we find out about it? –Where do we go? Literature Government agencies Scientific organizations Academe Other

16. Aspartame Uses Table-top sweeteners Instant beverages Carbonated soft drinks Juices Ice tea Dairy products Jams, marmalades Candies Cider,pickles, sauces Fish & fruit preservatives Chewing gums Multivitamins Ice Cream Puddings and jellies Chocolate Toothpaste, mouthwash Pharmaceuticals

17. Composition & Decomposition Aspartame molecule consists of 3 substances linked together –aspartic acid –phenylalanine –methanol When stored a long time or exposed to high temperatures it can break down –diketopiperazine (DKP)

18. Aspartame Concerns Cancer studies –Animal tests Special Groups in the Population –children, diabetics, people on weight reduction diets, lactating women, people who carry the gene for phenylketonuria Behavioral Effects –mood, behavior Possible Adverse Reactions –headaches, rashes, menstrual irregularities, other

19. History Discovered 1965 Originally approved by FDA in 1974 Clearance temporarily postponed--2 objections Evaluated by JECFA in 1980 & 81 Approved for dry food use in US 1981 Scientific Committee for Food 1985 UK Committee on Toxicity of Chemicals in Food, Consumer Products & Environment

20. How is aspartame regulated in your country now?

21. Paracelsus All substances are poisons; there is none which is not a poison. The right dose differentiates a poison and a remedy. No food substance is unequivocally safe or unsafe Safety depends on amount in diet

22. Food Safety Safe: Experts best judgment about the level of exposure to a substance that has reasonable certainty of no harm to humans under the intended conditions of its use. Terms –Acceptable Daily Intake (ADI) –Reference Dose

23. Food Safety Assessment Calculate Estimated Daily Intake (EDI) of substance Undertake toxicity studies of substance if needed Determine No Observed Adverse Effect Level (NOAEL) Select safety factor or uncertainty factor to extrapolate results from animals to humans Calculate Acceptable Daily Intake (ADI) Compare EDI and ADI

24. Estimated Daily Intake (EDI) Information on concentration of substance in food from chemical analyses, data on food processing, agency records, and so on. Consumer surveys estimate portion sizes and frequency of eating foods potentially containing substance (aspartame). Assumptions

25. EDI How can you get EDI information? What are the advantages/disadvantages of existing studies? Whose EDI do you want? –All people or just consumers of substance? –Median consumer or consumer of large quantities? –Young? Old? Immuno-compromised?

26. Intake Survey Types Recall Diary Duration

27. Design a Survey What do you need to be concerned about? –Population studied –Measurements necessary –Duration of study –Data analysis –Data interpretation

28. Population Studied General population –All –Consumers High intake groups Special groups –Children –Pregnant women –Diabetics

29. Measurements Necessary Quantitative intake of foods & beverages Special product types (e.g. low calorie) Specific brands Sweetener concentration differences

30. Duration of Study Human intake equivalent to safety study duration –Subchronic (90 days) –Chronic (lifetime) Actual studies limited –1-day studies common 7-day average a good compromise

31. Data Analysis % consumers in study population Source of intake, patterns of use Average intake consumers-only Mean, median and extreme consumers High consumers –90 th, 95 th or 97.5 th percentile

32. Level of Consumption How do we find out how much is in diet? Surveys and Assumptions –If Aspartame replaces all sucrose in US diet average is 8.3 mg/kg/day –If Aspartame replaces all carbohydrates average is 25 mg/kg/day –99th percentile of Aspartame consumption 34 mg/kg/day

33. Level of Consumption Monitor consumption –90th percentile 1984-89 1.6 to 2.3 mg/kg/day –99th percentile 5.8 to 6.5 mg/kg/day –99th percentile for all children US 3.0 to 8.3 mg/kg/day –95th percentile for children Canada 5.7 to 12.3 mg/kg/day

34. Level of Consumption –99th percentile diabetics US 8.0 to 8.3 mg/kg/day –95th percentile diabetics Canada less than 15 mg/kg/day How do these relate to the ADI?

35. EDI Using these data and what you know Identify an EDI Explain your choice –Strengths –Weaknesses

36. Toxicological Aspartame Data Over 100 studies Acute toxicity Sub-chronic toxicity Chronic toxicity Carcinogenicity Genotoxicity Reproductive toxicity, teratogenicity, fertility Special developmental studies Pharmacological studies

37. NOAEL No-observed-adverse-effects-level or No- observed-effects-level (NOEL) Biggest dose of chemical that produces no toxicity In toxicology, the highest dose at which no adverse effect is observed

38. Animal Studies Relatively high dose to relatively few animals Absence of data in low dose region Which mathematical model best approximates dose-response in low dose region Fit data that exists Linear extrapolation to zero from fitted curve or 95% confidence interval

39. Dose Response Linear Extrapolation Excess Tumor Rate Dosage Experimental Range Estimated Dose Response Upper Confidence Limit Linear Extrapolation Alternative Extrapolations Actual Data

40. Low Dose Response Two extrapolation problems –From animals to humans –From high dose to low dose Many mathematical models possible Alternative approach is to use safety factors or uncertainty factors

41. From NOAEL to ADI The NOAEL is an estimate for animals Need to get to humans

42. ADI Maximum acceptable daily intake (ADI) ADI is not an absolute limit that can never be exceeded ADI is an estimate of the amount of an additive that can be consumed daily for a lifetime without adverse effects Used to estimate population safety not individual safety

43. ADI Rules of Thumb Intakes predicted using conservative budgets present no problemactual intake data not necessary Intake data needed when intake could be close to ADI

44. Safety/Uncertainty Factors Multiply all factors that pertain to food safety assessment for overall safety factor ADI is the NOAEL divided by the safety factor NOAEL Safety Factor

45. Safety/Uncertainty Factors 10 for extrapolation of NOAELs obtained from chronic toxicity studies in animals to humans 10 for extrapolation of NOAELs obtained from subchronic toxicity studies in animals to humans 10 for extrapolation of NOAELs for severe irreversible endpoints from reproductive or developmental toxicity studies to humans 10 for sensitive populations 10 for children 10 for variability in the population

46. Safety Factor Identify relevant factors Justify your choice Calculate safety factor Using previous NOAEL calculate an ADI

47. Acute Toxicity Aspartame and DKP –Oral LD50 > 5000mg/kg in mouse, rat, & rabbit –NOAEL up to 10,000 mg/kg

48. Chronic/Sub Chronic Studies NOAEL Aspartame –Mouse ===> 4000 mg/kg/day –Rat======> 2000 mg/kg/day –Dog=====> 1000 mg/kg/day –Monkey==> 1000 mg/kg/day DKP –Mouse====> 1000 mg/kg/day –Rat======> 750 mg/kg/day

49. How Is This Done? Must every nation do its own toxicology? –This is same for all –Use what is available The Internet is a good source of these data You can begin your search at this web site

50. Use Whats Available Food Safety Risk Analysis Clearinghouse www.foodriskclearinghouse.umd.edu Joint Expert Committee on Food Additives http://jecfa.ilsi.org TOXNET http://toxnet.nlm.nih.gov

51. Use Whats Available WHO Regional Diets www.who.int/fsf/GEMS/index.htm WHO Food Safety www.who.int/fsf/ Intake studies http://www.foodriskclearinghouse.umd.edu/datab ases-ed1.htm#Food Intake

52. NOAEL Use evidence presented and what you may know Identify a NOAEL Explain your choice –Strengths –Weaknesses

53. FDA ADI Aspartame ADI set by FDA is 50mg/kg/day

54. JECFA ADI NOAEL = 4000 mg/kg body weight/day Safety factor = 100 ADI = 40 mg/kg/day 2400 mg daily for 60 kg adult (not an ADI) ADI for DKP = 7.5 mg/kg bw/day

55. Risk Characterization Using your EDI and ADI calculate the safety quotient Is the population with this EDI safe? Critique the technique –How many Conservative judgments did you make? –Strengths & Weaknesses

56. Sensitivity Analysis

57. Advantages of Safety Assessment Can be used relatively quickly to screen whether exposure to substance has potential adverse health effects. Consistent in data requirements and calculation of safety factors. It has a conservative bias.

58. Disadvantages of Safety Assessments May not use all available study data (for example, dose-response information) Does not quantify risk. –How likely is it to be unsafe? –What is the consequence? It has a conservative bias.

59. How Scientific Is Food Safety Analysis? Trans-science –questions which can be asked of science, yet which cannot be answered by science. Alvin Weinberg 1972

60. The End