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

1. Drug Residues in Milk and Milk Products Risk Assessment: Status and Current Thinking CAPT Wendy Fanaselle, USPHS, & Dr. Karin Hoelzer, FDA 4/29/2011

4. 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

5. 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

6. 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?

7. 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?

8. 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?

9. 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? 9

11. 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 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)

12. What is the potential drug residue concentration in raw milk delivered to the processor? Pictures from Alan Sayler, IDFA

13. 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

14. 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?

15. Consumer Health Effects Hazard & Potency

16. Hazard Characterization • Focus on available data on toxicological effects of drug(s) in humans • Based on two criteria: • Nature of the Hazard – determination of key acute effects and/or chronic effects for each drug/ class in humans • Potency of drug residue(s) - based on ADI from animal studies

17. Hazard Score Matrix

18. 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.

19. 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

20. 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.

21. 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

22. Excerpt from USDA, APHIS data on antimicrobial drug preferences on dairy farms 23

23. Combined Potency and Hazard Score

31. 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

32. 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

33. 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] 34

34. 4. Hazard Characterization Consequence of Human Exposure to a drugdepends on: Potency of drug: Level of exposure

35. 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.

36. 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. s

37. 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)

38. Example Acute and Chronic effects 39

39. 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

40. Data Gaps: ProcessingModule • 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

41. 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

42. 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

43. RA Clearance Process

44. RA Clearance Process

45. RA Clearance Process

46. RA Clearance Process

47. RA Clearance Process

48. RA Clearance Process Total: 791 Days; 2.2 Years

49. Risk 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 Acknowledgements

50. Thank You QUESTIONS ?