Drug Residues in Milk and Milk
Products Risk Assessment:
Status and Current Thinking
CAPT Wendy Fanaselle, USPHS,
& Dr. Karin Hoelzer, FDA
4/29/2011
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Risk Assessment is…
• systematic, dynamic & iterative
• a tool to understand the complex interaction of
hazards, food and human hosts
• one of the most objective and scientific ways to
• analyze the complexities of our food supply system
• focus our food safety efforts
• determine the relative effectiveness of prevention and
control practices
• an approach to integrate science with state-of-theart information technology to help manage food
safety risks
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Role of Risk Analysis in Public
Health Policy
A Powerful Public Health Tool
– Scientific basis for food safety policies and
allocation of resources
– Allows for transparency and stakeholder
involvement to ensure credibility and
scientific accountability
– Facilitates the application of science to
policy – “ informational bridge” between
data and decisions
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Risk Assessment
• A process to describe what we know
and how certain we are of what we
know
• Answers 4 key questions:
– What can go wrong?
– How likely is it to occur?
– What are the consequences?
– What factors can influence it?
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Key Questions to Answer:
• What drugs have the potential for administration
to dairy cattle and how likely is it?
• What is the potential extent, frequency, and
amount of drug use in dairy cattle?
• How likely is the drug to be present in raw milk
collected on the farm, and be delivered to the
processor, and what is the potential drug residue
concentration?
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Key Questions Continued:
• How do milk processing procedures impact drug
residue concentrations?
• What is the potential concentration of drug residues in
processed fluid milk and milk products?
• What is the potential level of consumption of the drug
residue by the consumer? Are those levels
acceptable?
• What are the relative potential impacts leading to
antimicrobial resistance and toxicological effects in
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exposed consumers?
Scope of the Risk Assessment
• Products of Concern: Which Milk Product?
• Hazards of Concern: Which Drug Residues?
• Endpoints of Concern:
– What Populations of Concern?
– What adverse effects are we characterizing ?
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Risk of Drug Residues
in
Milk & Milk Products
Exposure Assessment:
On-farm
drug use in
dairy cattle
Effect of processing
on drug residues in
milk & milk products
Consumer Health
Effects
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Risk Assessment Framework
On Farm
Module
Drug use in cows & frequency and levels of drug presence in raw milk
Processing
Module
Likelihood & magnitude of drug survival in products after processing
Consumer
Module
Magnitude of human exposure to drug via consumption of products
Hazard
For an ingested dose, what & how likely, is the adverse effect?
Characterization (Acute/Chronic)
Module
Risk Characterization: For each drug in milk products, a relative risk score based
on health consequences (likelihood & severity of illness) and potential exposure
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(likelihood and extent of exposure)
What is the potential drug residue
concentration in raw milk delivered
to the processor?
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Pictures from Alan Sayler, IDFA
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What is the potential drug residue
concentration in fluid milk and milk
products?
Whey Powder
Whey protein concentrate
Milk protein concentrate
Lactose
Dried Milk
Evaporated Milk
Condensed Milk
Butter
Cream
Buttermilk
Sour Cream
Whole Milk, 1%, 2%, & Skim Milk
Cheese
Cottage Cheese
Yogurt
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Effect of milk processing procedures on
drug residues
• Heat Tolerance: Drug melting point and
degradation temperature?
• Solubility: Is the drug protein bound, fat soluble, or
water soluble?
• Drying/Condensing/ Remove Water: Is the drug
still present after drying, condensing or other water
removal process?
• Drying/ Water removal: Is the drug still present in
whey protein powder?
• Fat removal Process: Is the drug still present
after fat removal processing?
• Enzymes/ Salt Added: Do enzymes or salt added
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have an impact on drug residues?
Consumer Health Effects
Hazard & Potency
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Hazard Characterization
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Focus on available data on toxicological
effects of drug(s) in humans
Based on two criteria:
1) Nature of the Hazard – determination of key
acute effects and/or chronic effects for each
drug/ class in humans
2) Potency of drug residue(s) - based on ADI
from animal studies
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Hazard Score Matrix
Chronic Effects
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c
u
t
e
E
f
f
e
c
t
s
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2
3
4
5
6
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Evide
nce of
Carco
genici
ty in
huma
ns
Irreversibl
e
neurotoxic
,
reproducti
ve or
teratogeni
c effects
Irreversible
organ toxicity
&
immunotoxico
logical
effects;
carcinogenic
or teratogenic
potential
Hematolo
gic
consequ
ences
(anemia,
bleeding,
ect.)
Rever
sible
organ
toxicit
y
(kidne
y or
liver)
Rev
ersi
ble
adv
ers
e
effe
cts
No
adv
ers
e
effe
cts
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Fatal anaphylaxis or irreversible
severe consequences commonly
reported (at low doses)
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20
18
16
15
15
15
15
2
Fatal anaphylaxis or irreversible
severe consequences sometimes
reported (at low doses)
2
20
18
16
12
12
12
12
3
Serious effects commonly
reported; high prevalence of IgEmediated allergy (>1% of total) in
population; rare fatalities
3
20
18
16
11
9
9
9
4
Common GI or constitutional
symptoms reported ; no evidence
of IgE-mediated rxns
4
20
18
16
11
9
6
5
5
Only mild adverse rxns reported;
no evidence of IgE-mediated rxns
5
20
18
16
11
9
6
6
No acute effects
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20
18
16
11
2
1
2
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What is Risk Ranking?
• A technique that can
be used to identify, &
thereby prioritize, the
most significant risks
for a given situation.
• Used when we have
multiple potential
hazards in foods
and need to know
which to focus on.
Risk Score for Drugs in Milk Product X
Drugs OnFarm
Proces Consu Hazard Total
sing
mer
A
15
15
20
25
75
B
5
30
35
20
90
C
25
10
15
15
65
D
20
0
0
0
20
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On-Farm Module
• Is a specific drug used in dairy cattle?
– Conditions the drug is used to treat
– Approval status, history, cost, and residue findings
• Extent of use:
– Proportion of herds using drug
– Proportion of animals per herd receiving drug
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On-Farm Module Continued:
• Amount & mode of administration per cow
– Frequency of need to use drug
– Drug dose per usage
– Mode of drug administration
Likelihood and magnitude of drug residue in raw
milk
– Drug discard time
– Time between drug administration and milking
– Dilution/Concentration.
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Estimation of Drug Usage in Dairy
Cattle and Subsequent Drug
Concentration in Milk
• Estimation is based on the following data:
– Dairy cattle production data – incl. herd size, milk production
(USDA, APHIS)
– Disease incidence data for dairy cattle (USDA, APHIS)
– Probability of different drug choices for treatment (USDA, APHIS)
– Expected fraction of herd treated (USDA, APHIS; other sources)
– Recommended dosage, duration and mode of administration
(multiple sources)
– Drug withdrawal time and probability of drug residue in bulk tank
milk (multiple sources incl. FDA data)
– Drugs approved for use in dairy cattle, identified through tissue
residue sample data, or otherwise submitted - incl. expert
judgment about drug availability and use (CFR; other sources) 22
Excerpt from USDA, APHIS data
on antimicrobial drug preferences
on dairy farms
Antimicrobial drug
Percentage of dairy farms using the drugs to treat these diseases/ health problems
Respiratory
Digestive
Reproductive
Mastitis
Lameness
Other diseases
Aminocyclitol
2.6 %
0.0 %
0.0 %
1.3 %
0.0 %
0.0 %
Aminoglycoside
0.0 %
1.3 %
0.0 %
0.0 %
0.0 %
0.0 %
Noncephalosporin beta-lactam
6.7 %
12.9 %
25.1 %
18.0 %
20.7 %
1.8 %
Cephalosporin
53.7 %
15.3 %
22.6 %
45.7 %
27.0 %
2.6 %
Florfenicol
2.4 %
0.0 %
0.0 %
0.0 %
0.4 %
0.0 %
Lincosamide
-
-
-
16.4 %
-
-
Macrolide
0.4 %
0.0 %
0.0 %
0.0 %
1.0 %
0.0 %
Sulfonamide
3.3 %
8.4 %
0.6 %
0.6 %
16.1 %
0.0 %
Tetracycline
9.3 %
3.0 %
24.4 %
5.7 %
12.1 %
0.0 %
Other drugs
3.0 %
2.2 %
3.0 %
1.5 %
3.3 %
0.0 %
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Combined Potency and Hazard Score
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Processing Module
Likelihood of drug residue in raw milk
• How do milk processing procedures affect
drug residues.
• Heat Tolerance
• Solubility
• Drying/Condensing/ Remove Water
• Fat removal Process
• Enzymes/ Salt Added
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Processing Module
• How does degradation impact drug residues?
• How does dilution and mixing impact drug
residues?
• OUTPUT: Likelihood of drug residue in milk
products
– Impact of processing, degradation and
dilution/mixing
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3. Consumer Module
Concentration (Cp)of drug residue in milk products [mg/kg]:
For each milk product
• For each identified population group determine:
– Frequency (f) of consumption of milk product [servings per day]
– Amount (q) of product consumed per serving - serving size
[grams/serving]
– Average weight (w) of an individual in the population in kgs.
OUTPUT: Daily exposure (E) per kilogram of body weight.
E = Cp * f * q / w [mg/kg/day]
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4. Hazard Characterization
• Consequence of Human Exposure to a drug
depends on:
– Potency of drug:
– Level of exposure
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4. Hazard Characterization
– Health Effects:
• Acute effects (eg. Allergenicity)
• Chronic effects (eg Carcinogenicity)
• Antimicrobial Resistance
– If the population considered is a susceptible or
sensitive population.
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Risk Characterization
• The risk is based on:
– Likelihood and magnitude of drug presence in
raw milk
– Likelihood and magnitude of drug survival thru
processing of milk products.
– Magnitude of human exposure to the drug via
consumption of milk products.
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Risk Characterization
• Consequence of Human Exposure
• If the population considered is a susceptible or
sensitive population.
• Potency of drug at the exposure level (dose
response)
• Health Effects manifested at exposure
level
• Drug acute effects (including allergies)
• Drug chronic effects (including
carcinogenicity)
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Example Acute and Chronic effects
CHRONIC EFFECTS
Evidence of carcinogenicity established in humans
Irreversible neurotoxic, reproductive or teratogenic effects in humans
Irreversible organ toxicity (kidney, liver) or ototoxicity; carcinogenic or teratogenic potential
Hematologic consequences (anemia, bleeding, etc.) and/or immunotoxicological effects
Reversible organ toxicity (e.g. kidney, liver) or neurotoxicity
Reversible adverse effects (e.g., blood pressure changes, etc.)
No adverse chronic effects known
ACUTE EFFECTS
High risk for fatal anaphylaxis or life threatening symptoms in general population
Moderate risk for fatal anaphylaxis; serious adverse symptoms commonly reported
Low but tangible risk for anaphylaxis and life-threatening reactions; High prevalence (>1%) of IgEmediated allergy
Common GI or moderate constitutional symptoms; Low prevalence (<1%) of IgE-mediated allergy
Only mild adverse reactions reported; no evidence of IgE-mediated reactions
No acute effects known
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Data Gaps: On Farm Module
– Off-Label Use of drugs in dairy cattle?
• Conditions the drug is used to treat, cost, mode of
administration, frequency of need to use, typical hold
time before milking, and residue findings
– Extent of use:
• Proportion of herds using drug, Proportion of animals
per herd using drug
– Drug residue concentrations in raw milk
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Data Gaps: Processing Module
– Impact of processing on drug residue
viability and concentration ?
– Impact of heat tolerance and solubility on
drug viability in products after water/fat
removal, or enzyme/salt addition.
– Impact of degradation, dilution, and
mixing
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Additional Issues to be Addressed
• Drugs with little information (i.e., not
used in humans)
• How to address/compare acute vs.
chronic effects?
• Hazard consequences
• Identifying sensitive populations
• How to address antimicrobial
resistance
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Procedure
• Phase 1: Commission the RA
– Charge
– Formed Joint CVM/CFSAN Risk Assessment and Risk
Management Teams
• Phase 2: Data Collection and Evaluation
– RA team reviewed and gathered data: Invited speakers
– Decide on approach “Risk Ranking”
• Phase 3: Develop Model and Report
• Phase 4: Review
– Internal risk manager review
– External peer review
• Phase 5: Revise and Finalize Report for Publication
– Submit for agency clearance
– Issue draft for public comment
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RA Clearance Process
Event
A
B
C
D
E
F
G
H
Days
Cum.
Review & Approval of RA Report/ Model for
Peer Review
Develop draft RA report/
model
Briefing for CFSAN
managers and others
X X
Review by Project’s Risk
Management (RM) Team
Revised Draft RA report/
model ready for peer reveiw
X
X
X
X
X
1
1
14
15
180
195
A= RA Team; B= RM Team, C= OFDCER, D= SSA, E= CFSAN, F= OMS,
G= OGC, H= Other for Review/ Clearance
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RA Clearance Process
Event
A B
C
D
E
F
G
H
Days
Cum.
External Peer Review
SOW/ Task Order Approval
in OMS and FDA Contracts
X
Submit to VERSAR for Peer X
Review
30
60
255
X
30
285
Revise RA report/ model, as X
necessary
60
345
Prepare peer review
summary report and post
on web
X
A= RA Team; B= RM Team, C= OFDCER, D= SSA, E= CFSAN, F= OMS,
G= OGC, H= Other for Review/ Clearance
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RA Clearance Process
Event
A
B
C
D
E
F
G
H
Days
Cum.
Clearance of Draft RA Report/ Model and FR
Notice for Public Comment
Approval: RM Team
X
Approval: OFDCER Director
X
Approval: SSA (OCD
designee)
X
Courtesy copy to: OF, IRAC,
CDC and other agencies
Draft RA report/Model & FR
notice to OGC for
review/clearance
7
352
14
366
14
366
0
X
X
60
426
A= RA Team; B= RM Team, C= OFDCER, D= SSA, E= CFSAN, F= OMS,
G= OGC, H= Other for Review/ Clearance
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RA Clearance Process
Event
A B
C
D
E
F
G
H
Days
Cum.
Public Comment & Response
Provide Report/Model & Ref.
to Dockets
X
X
7
433
Submit to IT for posting
report on CFSAN website
X
X
7
433
Publish FR notice
X
30
463
FR notice comment period
(90 days)
X
90
553
Review/ Respond to public
comments
X
60
613
Revise RA Report/Model as
necessary
X
90
703
A= RA Team; B= RM Team, C= OFDCER, D= SSA, E= CFSAN, F= OMS,
G= OGC, H= Other for Review/ Clearance
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RA Clearance Process
Event
A
B
C
D
E
F
G
H
Days
Cum.
14
717
7
724
7
15
Clearance & Approval of Revised RA
Report/ Model & FR Notice
Approval: RM Team
X
Approval: OFDCER Director
X
Clearance: SSA (OCD
Designee)
X
Courtesy copy to: OF, IRAC,
CDC & other agencies
FR Notice and Revised RA
Report/ Model to OGC for
review and clearance
0
X
X
30
761
A= RA Team; B= RM Team, C= OFDCER, D= SSA, E= CFSAN, F= OMS,
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G= OGC, H= Other for Review/ Clearance
RA Clearance Process
A B
Event
C
D
E
F
G
H
Days
Cum.
Publication
Prepare RA Report/
Model for Submission
to Dockets
X
Post Revised Docment
on Web
Publish FR Notice
7
X
7
1
X
30
791
A= RA Team; B= RM Team, C= OFDCER, D= SSA, E= CFSAN, F=
OMS, G= OGC, H= Other for Review/ Clearance
Total: 791 Days; 2.2 Years
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Acknowledgements
Risk Management/ Advisor Team
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Neal Bateller, CVM
Philip Bolger, CFSAN
Karen Ekelman, CVM
Ted Elkin, CFSAN
John Sheehan, CFSAN
Kim Young, CVM
Don Zink, CFSAN
Risk Assessment Team
• Johnny Braddy, CFSAN
• Deborah Cera, CVM
• Barry Hooberman, CVM
• Stefano Luccioli, CFSAN
• Amber McCoig, CFSAN
• Clarence Murray, III, CFSAN
• Ray Niles, CVM
• Michelle Stull, CVM
• Jane Van Doren, CFSAN
• Sandra Tallent, CFSAN
• Sherri Dennis, CFSAN
• Wendy Fanaselle, CFSAN
• David Oryang, CFSAN
• Karin Hoelzer, CFSAN
• Lori Papadakis, CFSAN
• Katie Sherman, CVM
• Tong Zhou, CVM
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Thank You
QUESTIONS ?
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