Drug Residues in Milk and Milk Products Risk Assessment: Status and Current Thinking

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Drug Residues in Milk and Milk Products Risk Assessment: Status and Current ThinkingCAPT Wendy Fanaselle, USPHS,

& Dr. Karin Hoelzer, FDA4/29/2011

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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-the-art 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 exposed consumers?

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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 Risk of Drug Residues in in

Milk & Milk ProductsMilk & Milk Products

Exposure Assessment: Exposure Assessment:

On-farmdrug use in dairy cattle

Effect of processingon drug residues in milk & milk products

Consumer Health Effects

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Risk Assessment FrameworkDrug use in cows & frequency and levels of drug presence in raw milk

Likelihood & magnitude of drug survival in products after processing

Magnitude of human exposure to drug via consumption of products

On Farm Module

Processing Module

Consumer Module

Hazard Characterization

Module

For an ingested dose, what & how likely, is the adverse effect? (Acute/Chronic)

Risk Characterization: For each drug in milk products, a relative risk score based on health consequences (likelihood & severity of illness) and potential exposure (likelihood and extent of exposure)

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What is the potential drug residue concentration in raw milk delivered

to the processor?

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 have an impact on drug residues?

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Consumer Health Effects

Hazard & Potency

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Hazard Characterization

• 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 MatrixChronic Effects

A

c

u

t

e

E

f

f

e

c

t

s

1 2 3 4 5 6 7

Evidence of Carcogenicity in humans

Irreversible neurotoxic, reproductive or teratogenic effects

Irreversible organ toxicity & immunotoxicological effects; carcinogenic or teratogenic potential

Hematologic consequences (anemia, bleeding, ect.)

Reversible organ toxicity (kidney or liver)

Reversible adverse effects

No adverse effects

1 Fatal anaphylaxis or irreversible severe consequences commonly reported (at low doses)

1 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 IgE-mediated 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 2

6 No acute effects 6 20 18 16 11 2 1 1

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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 On-Farm

Processing

Consumer

Hazard Total

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)

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Excerpt from USDA, APHIS data on antimicrobial drug preferences

on dairy farmsAntimicrobial 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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0.00

2.00

4.00

6.00

8.00

10.00

12.00

14.00

Additive Combined Potency and Hazard Score Root Mean square Combined Potency and Hazard Score

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 ModuleConcentration (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 [g/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

ACUTE EFFECTSHigh 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 IgE-mediated 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

CHRONIC EFFECTSEvidence 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

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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 ProcessEvent A B C D E F G H Days Cum.

Review & Approval of RA Report/ Model for Peer ReviewDevelop draft RA report/ model

Briefing for CFSAN managers and others

X X X X X 1 1

Review by Project’s Risk Management (RM) Team

X 14 15

Revised Draft RA report/ model ready for peer reveiw

X 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 ProcessEvent A B C D E F G H Days Cum.

External Peer ReviewSOW/ Task Order Approval in OMS and FDA Contracts

X 30

Submit to VERSAR for Peer Review

X X 60 255

Prepare peer review summary report and post on web

X 30 285

Revise RA report/ model, as necessary

X 60 345

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 ProcessEvent A B C D E F G H Days Cum.

Clearance of Draft RA Report/ Model and FR Notice for Public CommentApproval: RM Team X 7 352

Approval: OFDCER Director X 14 366

Approval: SSA (OCD designee)

X 14 366

Courtesy copy to: OF, IRAC, CDC and other agencies

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Draft RA report/Model & FR notice to OGC for review/clearance

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 ProcessEvent A B C D E F G H Days Cum.

Public Comment & ResponseProvide 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 ProcessEvent A B C D E F G H Days Cum.

Clearance & Approval of Revised RA Report/ Model & FR Notice

Approval: RM Team X 14 717

Approval: OFDCER Director X 7 724

Clearance: SSA (OCD Designee)

X 7 15

Courtesy copy to: OF, IRAC, CDC & other agencies

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FR Notice and Revised RA Report/ Model to OGC for review and clearance

X X 30 761

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 ProcessEvent A B C D E F G H Days Cum.

Publication

Prepare RA Report/ Model for Submission to Dockets

X 7

Post Revised Docment on Web

X 7 1

Publish FR Notice 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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AcknowledgementsRisk Management/ Advisor Team• 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 ?