Maximum Residue Limits

Maximum Residue Limits a scientific approach to ensure consumer safety ànd (food) animal health Prof Dr Erik De Ridder 1

Residues & safety: ADME Metabolism Distribution Excretion Administration Absorption 2 ADME Change of druglevels (residues) over time

When you treat a food animal Residues present for some time Potential problem for consumer 3

Hazard and risk: risk assessment basics 4

Hazard and risk when treating food animals Hazard? Residues of the drug after a treatment still being present at the time of slaughter (or production of milk, egg, honey) Risk? Risk assessment: What is the risk that harm will be done by remaining residues? Or: what would be the level of residues that would not be harmful? Or: what is the Maximum Residue Level acceptable? Risk Management? Risk management: How can we manage so that risk remains acceptable? Or: what is the withdrawal period after treatment? 5

6 Legal basis in the EU

Safety of residues? Is zero-residue an option? Why (not)? 7

How can a treated animal safely enter the human food chain? With an MRL or Maximum Residue Level! Zero residue? No option, because related to LOD & LOQ of method! Alternative: can you determine a level of residue that can be safely consumed, every day of your life: a chronic ingestion approach: that is the Maximum Residue Limit or MRL approach 8

How to establish MRLs? Human studies forbidden, so scientific risk assessment required Chronic intake tox studies in animals! Basis to assess safety Pharmacology critical to understand: Marker residue or residue of concern? Parent, conjugate and / or metabolite(s)? Residue depletion Need analytical method to detect the marker residue validated in all tissues 9

How can a treated animal safely enter the human food chain? With an MRL or Maximum Residue Level! An MRL should be set for each edible tissue and is in principle species-specific muscle, fat, liver, kidney, milk, honey, eggs because ADME is species and tissue specific! MRL vs. Withdrawal period MRL = safe level of residues in food! Withdrawal time: When after treatment are residue levels safe? 10

Safety of residues? The route to MRLs NOEL ADI MRL Withdrawal Period what is a safe level in the most sensitive animals what is the safe amount of residues that humans can consume every day? how much residue can be in each type of animal produced food? when can I be sure that the food is safe? 11

Assessment of safety: NOEL and ADI For each study: no observed (adverse) effect level (NOEL), in mg/kg/day Lowest NO(A)EL from each set of studies Safety factor, ranging from 10 to 2000, depending on quality of the data and the type of the effect observed 10x10: inter- and intraspecies variation 10 or 20 if mutagenicity or teratogenicity Acceptable Daily Intake (ADI) estimates safe intake level: ADI = NOEL (mg/kg bw/day) x 60kg BW Safety factor 12

Determination of (which) ADI Toxicological ADI (animal chronic tox data) Microbiological ADI (effects on human gut flora): MIC, bioavailabilty, ADME Disruption of the colonization barrier Increase of the population(s) of resistant bacteria Complex set of studies: VICH GL36 Same concept of safety factors Pharmacological ADI: Data from human use or models, safety factors The lowest of the 3 is the final ADI! You can consume this amount every day of your life without any effects on your health 13

Safety of residues? The route to MRLs NOEL ADI MRL Withdrawal Period what is a safe level in the most sensitive animals what is the safe amount of residues that humans can consume every day? how much residue can be in each type of animal produced food? when can I be sure that the food is safe? 14

From safety to residues From an ADI we know IF a molecule can be used safely in a veterinary medicinal product Daily food consumption multiple types of animal derived food need to determine safe concentration of residues in each potential tissue that can be consumed daily food basket ADI ADI distributed over all types of food But first: what residues should we look at? 15

Towards safety of residues What studies are typically required? For setting the safe concentration or MRL Basic Toxicology Studies Comparative Metabolism-Toxicology Species Total Residue and Metabolism-Target Species Analytical Method For setting the withdrawal time Residue Depletion in the target Species 16

Comparison of metabolic profiles Basic question: did we study the right compound(s) in our toxicology studies in lab species? Qualitative comparison of metabolic profiles in lab species and the target species from Outcome (hopefully) : yes Impact? if profiles are not comparable, more toxicology testing may be indicated 17

Total Residue and Metabolism Study? What? Radiolabeled drug 1-1.5X the proposed dose Proposed route of administration Intended duration of treatment/steady state Intended species; males and females 18

Total Residue and Metabolism Study: why? Determines the MARKER RESIDUE = the residue that monitors the depletion of total residues in a tissue Determines the TARGET TISSUE generally, the edible tissue from which residues deplete most slowly often, liver or kidney rarely, muscle or fat Regional differences In US typically tolerance set on the target tissue In EU typically MRL set for all tissues 19

Total Residue and Metabolism Study: outcome? Provides the METABOLIC PROFILE in the foodproducing animal for comparison with the toxicological lab-species Establishes the MARKER:TOTAL ratio MARKER Residue TOTAL Residue Used to calculate actual exposure to residues worst case scenario Correction factor for cold depletion studies with marker residue 20

Analytical Methodology Why is this required? Determinative: demonstrate you can find it! measures concentrations of drug residues in tissue Confirmatory: demonstrate you can tell it was indeed the marker residue that was found verifies the identity of the drug residue Regulatory agencies and inspectorates must be able to find the residues! 21

Analytical method Validated analytical method Concentration range: ½ MRL, MRL, 2xMRL Specificity, accuracy, precision LOQ and LOD Applicability and practicability Stability of the analyte (residue) during sample storage and handling 22

From residues to consumption Some definitions used internationally TDMI: Theoretical Daily Maximum Intake The TDMI is calculated by multiplying the average per capita daily food consumption for each food by the maximum use level established by national regulations or by the proposed use levels by the animal health industry and summing the resulting exposure values to give total dietary exposure. Estimated Daily Intake (EDI) the amount ingested by the average consumer of the food based on the actual use, or an approximation as close as possible to the actual uses levels. 23

From residues to consumption Now we know The right marker residue and marker tissue How much of the total residue is marker residue Now we need to determine how much can be present in the different tissues Remember: SAFE CONCENTRATION The safe concentration is the amount of residue that can be eaten in any edible tissue each day for an entire lifetime without exposing the consumer to residues in excess of the ADI Need to distribute the ADI over all animal-derived food you can eat in a day Need a food basket : What do we eat on a daily basis? 24

From residues to consumption Here are the assumptions A healthy adult eats a daily ration containing: 1.5 kg milk(products); 300 g lean meat; 100 g liver; 50 g kidney; 2 eggs; 50 g (animal) fat and 20 g honey If you do this daily you probably look bigger than a sumo wrestler please consult your doctor urgently Why is the food basket than so big? 25

From residues to consumption Some differences Species: eg poultry, fish, honey-bees,... Do we eat all? 26

From residue and consumption to MRL (EU) 0,05 kg x 20 µg/kg 0,05 kg x 20 µg/kg x 3,95 = 3,95 = 3,95 µg µg 0,253 0,3 kg x 10 µg/kg 1 = 3 µg MRL proposed marker/ total residu Residue present in Edible Tissue Daily intake(kg) (µg/kg) ratio* food (µg) Muscle 0.300 10 1 3.00 Fat 0.050 20 0.253 3.95 Liver 0.100 100 0.131 76.34 Kidney 0.050 20 0.331 3.02 Eggs 0.100 150 0.357 42.02 Total Consumption or TDMI 128.33 ADI 150 % ADI used 85.55% * Ratio Marker/Total around time that total residue gets around 100% of ADI 27

EU approach on MRLs: using depletion studies Depletion studies for all tissues 28

Use of residue data: EU approach on MRLs best time to set ratio of marker to total residues 29

From residue and consumption to MRL (EU) Edible Tissue Daily intake(kg) MRL proposed (µg/kg) marker/ total residue ratio* Residue present in food (µg) Muscle 0.300 10 1 3.00 Fat 0.050 20 0.253 3.95 Liver 0.100 100 0.131 76.34 Kidney 0.050 20 0.331 3.02 Eggs 0.100 150 0.357 42.02 Total Consumption or TDMI 128.33 ADI 150 % ADI used 85.55% * Ratio Marker/Total around time that total residue gets around 100% of ADI 30

Classification of substances & final MRL s Previously (Reg 2377/90) Annex I: final MRLs Annex II: no MRLs needed no residues/natural substances/no concern Annex III: provisional MRLs, with expiry date Annex IV: prohibited in food producing species Currently (Reg 37/2010): Allowed Prohibited Out of scope list: mainly excipients Demonstrate absence of pharmacological activity Can be withdrawn (cfr paraben issue) 31

32 Table 1: Allowed substances

33 Tabel 2: Prohibited substances

34 Special entry 1: all food producing species

35 Special entry 2: no MRL required

Safety of residues? The route beyond MRLs NOEL ADI MRL Withdrawal Period what is a safe level in the most sensitive animals what is the safe amount of residues that humans can consume every day? how much residue can be in each type of animal produced food? when can I be sure that the food is safe? 36

When can a treated animal enter the food chain? When: as soon as residue depletion falls below MRL for every tissue after use of the product Concept of withdrawal times required (WT or WHP) Don t let treated animals enter the food chain until the withdrawal time has been respected Via residue depletion study, focused on the marker residue Time between administration and depletion of residues below MRL, plus safety factor through regression, 95% Upper Tolerance Limit of the 95th Confidence interval 37

When can a treated animal enter the food chain? EU: Via residue depletion study, focused on the marker residue MRL proposed by industry, decided by government Food basket used afterwards to calculate TDMI Time between administration and depletion of residues below MRL, plus safety factor through regression, 95% Upper Tolerance Limit of the 95% Confidence interval USA: also residue depletion study, focused on the marker residue in the target tissue Tolerance is Safe concentration cold residue x marker/total residue ratio 99% Upper Tolerance Limit of the 95% Confidence interval Directly linked to consumption factor or food basket Often higher than EU MRL Dairy products always get around 50 % of the ADI attributed 38

39 Why the upper tolerance limit of a confidence interval?

Special remarks Outliers can only be excluded under very strict conditions Impact of variation in data-set, especially when occurring at the ends of the observations Alternative approach allowed if UTL approach impossible e.g. all data points under MRL, even at d 0 e.g. flat slope leading to unrealistic or impossible WT Always WT for carcass (meat, fat, skin) Milk, eggs & honey have separate WT s Based upon the specific MRL s 40

MRL, WHP and the precautionary principle MRL & WT are classic examples of the so-called precautionary principle What safety factors are built in? 41

Steps in the establishment of an MRL Safety factors 1a. Toxicology studies in a panel of test species to find the noobserved-effect-level 1b. Safety Factor applied to NOEL before calculating acceptable daily intake (ADI) 2a. ADI shared out among the food items in a Standard Diet 2b. MRL set for each item in the standard diet so ADI not exceeded NOEL ADI Standard Diet MRL 1a. Use of the most sensitive test species to identify the NOEL 1b. Selection of the last test level to show no effect as the NOEL (i.e. not the true NOEL) 2. Safety factor (x100 or x1000) always applied to the NOEL 3. The Standard Diet represents the upper limits for each food commodity 4. Assumption: people eat the entire Standard Diet every day 5. Assumption that full ADI could be eaten every day of your life 6. ADI usually not 100% used for MRLs 3. Residue depletion studies (with formulated product) Withdrawal Time 7. Calculation of the withdrawal period with high safety margin 42

Summary of consumer safety concept NOEL ADI Food basket (assumed consumption) MRL Withdrawal time All subsequent steps in balanced and scientifically driven risk management 43

Regulatory aspects Food safety is top priority in the EU (and everywhere) No molecule can be registered for use in food producing species without food safety assessment (MRL) MRLs are set by CVMP upon request from: Industry applicant Member State(s) Commission Interested party or organisation (MUMS) If residues above the MRL are found: no entry into food chain 44

Consumer safety: 2 dossiers! MRL-submission: active substance Safety file: focus on consumer safety aspects Residue file : focus on possibility of a safe WT Outcome: ADI, MRLs and analytical method established Application for marketing authorisation: product Safety file Partly refers to MRL dossier Focus on other product safety aspects (TAS, ERA, user safety) Residue file Partly refers to MRL-dossier (or established MRLs) Focus on residue depletion after use of product Outcome: warning statements if required, and withdrawal time(s) 45

Reference points of action How do you handle controls on food imported into EU? May contain substances without (European) MRL, used in other parts of the world Commission decision: based on the LOQ of a validated analytical method, advice by Community reference laboratory Risk assessment by the EFSA may be requested Note: MRLs: responsibility of CVMP Residues above reference point of action: no entry into food chain 46

Safety of residue consumption? The route via MRLs NOEL ADI MRL Withdrawal Period what is a safe level in the most sensitive animals what is the safe amount of residues that humans can consume every day? how much residue can be in each type of animal produced food? when can I be sure that the food is safe? 47

Maximum Residue Limits a scientific approach to ensure consumer safety ànd (food) animal health Prof Dr Erik De Ridder 48