Aspartame Risk AssessmentFood Safety Analysis Exercise

Charles Yoe, Ph.D.College of Notre Dame of Maryland

Food Additives

• Chemicals added to food in small amounts– Direct additives– Indirect additives

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

Indirect Additives

• Enter food incidentally during– Handling– Processing (equipment)– Packaging

Is aspartame safe?

Risk Analysis

RiskAssessment

RiskManagement

RiskCommunication

Why Do Risk Analysis?

• To improve decisions• To help assure a safe domestic food supply• It’s essential for international trade• To enable industry to innovate• Because we have to

Risk Assessment

• What can go wrong?• How can it happen?• How likely is it?• What are the consequences?

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?

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?

Food Additive Safety Analysis

Amount of substance consumed Safe amount of substance

>1 => not safe = 1 => safe< 1 => safe

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

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

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

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

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

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)

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

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

How is aspartame regulated in your country now?

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

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

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

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

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?

Intake Survey Types

• Recall• Diary• Duration

Design a Survey

• What do you need to be concerned about?– Population studied– Measurements necessary– Duration of study– Data analysis– Data interpretation

Population Studied

• General population– All– Consumers

• High intake groups• Special groups

– Children– Pregnant women– Diabetics

Measurements Necessary

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

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

Data Analysis

• % consumers in study population• Source of intake, patterns of use• Average intake consumers-only• Mean, median and extreme consumers• High consumers

– 90th, 95th or 97.5th percentile

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

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

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?

EDI

• Using these data and what you know• Identify an EDI• Explain your choice

– Strengths– Weaknesses

Toxicological Aspartame Data

• Over 100 studies• Acute toxicity• Sub-chronic toxicity• Chronic toxicity• Carcinogenicity• Genotoxicity• Reproductive toxicity, teratogenicity, fertility• Special developmental studies• Pharmacological studies

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

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

Dose Response Linear Extrapolation

ExcessTumorRate

Dosage Experimental Range

EstimatedDose

Response

UpperConfidence

Limit

Linear Extrapolation

AlternativeExtrapolations

Actual Data

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

From NOAEL to ADI

• The NOAEL is an estimate for animals• Need to get to humans

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

ADI Rules of Thumb

• Intakes predicted using conservative budgets present no problem—actual intake data not necessary

• Intake data needed when intake could be close to ADI

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

Safety/Uncertainty Factors• 10 for extrapolation of NOAEL’s obtained from

chronic toxicity studies in animals to humans• 10 for extrapolation of NOAEL’s obtained from

subchronic toxicity studies in animals to humans• 10 for extrapolation of NOAEL’s 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

Safety Factor

• Identify relevant factors• Justify your choice• Calculate safety factor• Using previous NOAEL calculate an ADI

Acute Toxicity

• Aspartame and DKP– Oral LD50 > 5000mg/kg in mouse, rat, &

rabbit– NOAEL up to 10,000 mg/kg

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

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

Use What’s 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

Use What’s Available

• WHO Regional Dietswww.who.int/fsf/GEMS/index.htm

• WHO Food Safetywww.who.int/fsf/

• Intake studieshttp://www.foodriskclearinghouse.umd.edu

/databases-ed1.htm#Food Intake

NOAEL

• Use evidence presented and what you may know

• Identify a NOAEL• Explain your choice

– Strengths– Weaknesses

FDA ADI

• Aspartame ADI set by FDA is 50mg/kg/day

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

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

Sensitivity Analysis

Optimistic Pessimistic Most Likely

EDI 1.6 34 2.3

NOAEL 10000 1000 4000

Safety Factor 100 10000 1000

ADI 100 .1 4

EDI/ADI 0.016 340 .575

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.

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.

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

The End