Transcript Aspertame Risk Analysis Exercise

Aflatoxin Risk Assessment
“Red Book” Model Exercise
Charles Yoe, Ph.D.
College of Notre Dame of Maryland
Risk Analysis
Risk
Assessment
Risk
Management
Risk
Communication
Risk Assessment
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What can go wrong?
How can it happen?
How likely is it?
What is the magnitude of the effect?
What are the steps?
• CODEX
– Hazard identification
– Hazard
characterization
– Exposure assessment
– Risk characterization
• NAS
– Hazard identification
– Dose-response
assessment
– Exposure assessment
– Risk characterization
Risk Assessment CODEX
• Hazard Identification
– The identification of known or potential health effects
associated with a particular agent.
• Hazard Characterization
– The qualitative and/or quantitative evaluation of the
nature of the adverse effects associated with biological,
chemical, and physical agents which may be present in
food. Dose-response assessments should be performed
if the data are available.
Risk Assessment CODEX
• Exposure Assessment
– The qualitative and/or quantitative evaluation
of the degree of intake likely to occur.
• Risk Characterization
– Integration of hazard identification, hazard
characterization and exposure assessment into
an estimation of the adverse effects likely to
occur in a given population, including attendant
uncertainties.
Risk Assessment NAS
• Hazard Identification
– Determine if exposure to an agent causes an
increased incidence of an adverse health effect.
• Dose-Response Assessment
– Characterize the relationship between exposure
(at different levels or doses) and the incidence
of the adverse health effect.
Risk Assessment NAS
• Exposure Assessment
– Measure or estimate the intensity, frequency,
and duration of actual or hypothetical exposures
of humans to the identified agent
• Risk Characterization
– estimate the probability of specific harm to an
exposed individual or population based on
information from dose-response and exposure
assessments.
Turkey X Disease
• 1960 1000’s turkey poults died in England
• Major investigation
• Turkeys poisoned by agent in peanut meal
component of their feed
• Agent found in peanuts contaminated with
certain mold
• Mold, Aspergillus flavus, not responsible
for poisoning
Turkey X Disease
• 1965 MIT team solved mystery of turkey X
• Aflatoxin discovered
Mycotoxins
• No awareness of mold-related disease before
1960s
• Imported peanut meal killed 1000s of turkeys in
England 1960s
• The mold Aspergillus flavus produced toxins that
fluoresced under analysis
– aflatoxin blue (AFB)
– aflatoxin green (AFG)
• Over 100 mycotoxins identified since aflatoxin
Molds and Mycotoxins
• Considerable worldwide significance
– Public health
– Agriculture
– Economics
• Aflatoxin cost $20M to US peanut crop
1989
• Foods that are ground present particular
problems
What do we know about aflatoxin?
Aflatoxin
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Mixture of 4 closely related chemicals
Two emit blue fluorescence: B1 & B2
Two emit green fluorescence: G1 & G2
Research showed them regularly
– peanuts & some peanut products
– corn
– nuts
• Fed to animals can show up in derived food
products
Aflatoxin
• Experimental studies showed
– potent liver poison
– malignant tumors in rats, ferrets, guinea pigs,
mice, monkeys, sheep, ducks, trout
• Results reported 1961-1976
• Low level but not infrequent contaminant of
some human foods
Some Questions About Aflatoxin
• What is to be done?
• Are aflatoxins a threat to public health?
• How many cancers can be attributed to
them?
• Why is there no clear link to human
cancers?
• If a menace, how can we control it?
• How much of our resources is this worth?
Aflatoxicosis
• Poisoning from mold-produced metabolites
• Affects all tested species and humans
• Occurs when food supplies are limited and
people ate moldy grains
• Flabby heart, edema, abdominal pain, liver
necrosis, palpable liver
• Chronic ingestion--liver tumors
FDA and Aflatoxin
• Decided limits were in order, based on what
could be detected
• 1968 >30 ppb in peanut products unfit
• Lowered to 20 ppb soon after
• No completely safe level can be established
for cancer causing chemicals
• Does this mean as science gets better food
becomes less safe?
FDA and Aflatoxin
• Meeting 20 ppb not too great a burden on
peanut butter industry
– discolored peanuts could be eliminated by
sorting machines
– required substantial new quality control
measures
• Did this make scientific sense?
– If aflatoxin can be detected it is unacceptable if
it cannot it is acceptable
Yes
• Potent cancer causing agent in animals
• Do not wait for human data to control it
• Animal tests are reliable indicators of
human risk
• Risky at any level of intake
• Eliminate human exposure or reduce it to
lowest possible level
No
• Animal cancers occur at levels well above FDA
limit
• Provide some safety to humans but 20 ppb is too
low
• Policy of no safe level is not supported by science
• Animals not proven reliable indicators of human
risk
• Carcinogenic potency highly variable among
species
• No evidence of cancer in humans
FDA and Aflatoxin
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Easy to detect 5ppb in some labs
1 ppb almost routine in some labs
FDA did not call for these lower limits
Large fraction of peanut butter would fail 1
ppb standard
• Economic impact of 1ppb could be very
large
Detection
• Analytical chemists can now measure levels
toxicologists are unable to evaluate for
biological significance
• 1 ppm is like a second in 11.6 days
• 1 ppb is a second in 32 years
• 1 ppt is a second in 3,169 years
ppb
• Weight of contaminant divided by weight of
food
• In kg of peanut butter, 20 ppb is 20
micrograms
Aflatoxin Occurrence 1989
Food
US peanut
butter
Phil. p.b.
US corn
Phil. Corn
Wheat flour
Brazil nuts
Incidence
17/104
g/kg
14
145/149
49/105
95/98
20/100
123/300
213
30
110
.25-150
na
A Few More Points
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Corn responsible for most human exposure
Peanuts and peanut butter in US
Drought and other damage encourage mold
Heat not enough to destroy mycotoxin
Processing not effective in destroying
mycotoxins
• Preventing formation is crucial
Aflatoxin and Peanuts
• Average concentration in peanuts and
peanut butter is 2 ppb
• FDA defect action level (DAL) to seize
peanuts is 20 ppb
• In practice anything over 15 ppb is rejected
• Average daily intake estimate is 0.005 ppb
from peanuts
Science and Economics
• Just how certain is our science on matters
like this?
• Size of economic consequence should not
influence scientific thinking, but it
influences scientists and policy makers
when there are scientific uncertainties
Aflatoxin Management Options
• Constant testing
– more in drought years
• Seize contaminated crops
• Destroy contaminated crop residues
• Agricultural techniques
– forced air drying of crops
– controlled storage conditions
• Minimize exposure to moldy foods
Let’s look at a CODEX/NAS
risk assessment
Hazard Identification
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Evolving understanding
Turkey X
JECFA 1987
JECFA 1997
JECFA 1987
• Evaluated at 31st meeting of JECFA 1987
• Considered potential human carcinogen
• Insufficient information to set tolerable
intake level
• Urge reduction to lowest practicable level
JECFA 1997
• One of most potent mutagenic and carcinogenic
substances known
• Liver cancer in most species
• Some evidence humans are at lower risk than
other species
• Epidemiological studies show no detectable
independent risk
• Ongoing studies--Shanghai, Thailand, Qidong
JECFA 1997
• Hepatitis B virus may increase liver cancer
risk
• Estimated 50 to 100% of liver cancers are
associated with Hepatitis B
What is the hazard?
Hazard Identification
• The Committee considered that the weight of
scientific evidence, which includes
epidemiological data, laboratory animal studies in
vivo and in vitro metabolism studies, supports a
conclusion that aflatoxins should be treated as
carcinogenic food contaminants, the intake of
which should be reduced to levels as low as
reasonably achievable
• Source JECFA 1997
Hazard Characterization
• We will use a simple dose-response analysis
• This makes the two models, CODEX and
NAS essentially equivalent
Aflatoxin Toxicity
• B1 (AFB1) most common, most studied,
most toxic
• Toxicity varies by species
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LD50 .5 mg/kg for duckling
LD50 60 mg/kg for mouse
Binds to nucleic acids in some species
Difficult to assess for humans
• Death usually from liver damage
Dose-Response Analysis
• Limitations of available aflatoxin data
– Confounded by concurrent Hepatitis B
– Reliability & precision of aflatoxin exposure in
study population are unknown
– Shape of dose-response relationship unknown
Sources of Information
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Animal bioassays
Human feeding trials
Epidemiological data
Cell lines (tissue cultures)
• Animal studies most common for cancers
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
Interpolation
Upper
Confidence
Limit
Excess
Tumor
Rate
Linear
Extrapolation
Dosage
Alternative
Extrapolations
Experimental Range
Actual Data
Estimated
Dose
Response
Low Dose Response
• “Threshold/No threshold” assumption is
significant
• Many mathematical models possible
• Determines potency estimate
• Does not rely on safety factors
Dose-Response
• Potential biases in potency
– Only studies with + association were used
– Historical levels ignored in favor of current
levels of intake
– Hepatitis B prevalence systematically
underestimated in early studies
– Non-primary liver cancers may have been
included
– Interpolation method
Dose-Response
• Population risks
• Vary from population to population
– Geographically
– Culturally--diet
– Susceptibility--base health
Dose Response Factors
• Diet also affects toxicity
• Human response variable
– males and children more susceptible
• Hepatitis B increases cancer risk
Potency Values
• HbsAg+
• 0.3 cancers/year per
100,000 population
per ng aflatoxin/kg bw
per day
• Uncertainty range 0.05
to 0.5
• HBsAg• 0.01 cancers/year per
100,000 population
per ng aflatoxin/kg bw
per day
• Uncertainty range
0.002 to 0.03
Exposure Assessment
• Estimating frequency and intensity of
exposure to agent
• Magnitude, duration, schedule and route of
exposure
• Size, nature and class of exposed population
• Detailing associated uncertainties
Aflatoxin Exposure Assessment
• Contamination levels data appear biased
• Studies focus on commodity lots thought
contaminated
• Contamination levels must be used with
caution for patterns of importance not exact
contamination estimates
CDF Aflatoxin in US Maize
Contamination (µg/kg)
1000
100
10
1
0.01
0.1
0.2
0.3
0.4
0.5
0.1
0.01
Cumulative density
0.6
0.7
0.8
0.9
0.95
0.975
1
Hypothetical Standards
• Assume 20 µg/kg rejection level
– 4% maize crop rejected
– mean aflatoxin level of 0.91 µg/kg
• Assume 10 µg/kg rejection level
– 6.2% maize crop rejected
– mean aflatoxin level of 0.58 µg/kg
• Standards remove most highly
contaminated , reducing average
Risk Characterization
• Combine dose-response and exposure
assessments
• Describe risk in meaningful and useful
fashion
Cancer Incidence
• Combine
– Aflatoxin potency estimates (risk per unit dose)
• Dose response
– Estimates of aflatoxin intake (dose per person)
• Exposure
• What are the uncertainties in these
analyses?
Let’s do a simple risk assessment.
Sample Data and Assumptions
• Assume:
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Low contamination of food
Small prevalence of hepatitis B (1% carriers)
Potency = .3 with HBSAG+
Potency = .01 with HBSAGEuropean diet intake = 19 ng/person per day
Adult human weighs 60 kg
Population of 30 million
Aflatoxin Risk Assessment
• 1) Calculate estimated population potency
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a) What is potency for HBSAG+?
b) What is % of HBSAG+?
c) What is potency for HBSAG-?
d) What is % of HBSAG-?
e) ab + cd = population potency
Aflatoxin Risk Assessment
• 2) Calculate intake per kg bw
– a) What is intake per person?
– b) What is weight of a person?
– c) a/b
• 3) Calculate increased cancer rate due to
aflatoxin
– a) 1e x 2c
Aflatoxin Risk Assessment
• 4) Calculate increased number of cancers
– a) What is cancer rate?
– b) What is population
– c) ab
• 5) Repeat calculations for uncertain range
of potency
Calculate Cancers per Year
• 0.01 x 99% + 0.03 x 1% = 0.013 cancers/year per
100,000 population per ng aflatoxin/kg bw per day
• Range in cancer deaths is 0.002 to 0.035
• 19 ng/person per day  60 kg bw per person =
.317 ng/kg bw per day
• .317 ng/kg bw per day x 0.013 cancers/year per
100,000 population per ng aflatoxin/kg bw per day
= 0.0041 cancers/year per 100,000 people
Calculate Cancers per Year
• 30,000,000 people x 0.0041 cancers/year
per 100,000 people = 1.23 cancers/year
Risk Assessment Model
• Which steps were hazard identification?
• Which steps were dose-response
assessment?
• Which steps were exposure assessment?
• Which steps were risk characterization?
Model Comparison
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Food safety vs... CODEX/NAS Model
Did food safety have four steps?
What were major differences?
What were similarities?
Which was easier? Why?
Which do you prefer? Why?
Let’s see how we can address
the uncertainty in a model like
this.
Aflatoxin Exercise
Data Input
Prevalence of Hepatitis B
Minimum
Most Likely
Maximum
Potency with HBsAG+
Minimum
Most Likely
Maximum
Potency with HBsAGMinimum
Most Likely
Maximum
Diet intake
Minimum
Most Likely
Maximum
Adult human weight
Minimum
Most Likely
Maximum
Population
Minimum
Most Likely
Maximum
Deterministic Calculations
Population Potency
Aflatoxin Exposure per kg BW
Aflatoxin Cancer Rate
Cancer Deaths
European Diet
Far Eastern Diet
0.50%
1.00%
3.00%
20.00%
25.00%
35.00%
0.05
0.3
0.5
0.05
0.3
0.5
0.002
0.01
0.03
0.002
0.01
0.03
5
19
45
60
125
200
55
60
100
50
60
80
95000000
100000000
110000000
95000000
100000000
110000000
0.0129
0.3167
0.0041
4
0.0825
2.0833
0.1719
172
Model With Uncertainty
Population Potency
Aflatoxin Exposure per kg BW
Aflatoxin Cancer Rate
Cancer Deaths
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What’s Next?
• Once the risk has been assessed
– Risk management decides what to do about it
– Risk Communication
• The risk is described to others
• Management options are explained
The End