Residues Mike Apley, DVM, PhD
Residues: It s Black and White Residues occur when detected concentrations of the marker residue are above the approved tolerance for that drug in that tissue. Residues are monitored in target tissues; the tissues which hold the residue the longest. These tissues indicate the status of other edible tissues in the animal. So, how does the FDA/CVM decide what is acceptable and what is not?
First, the basics Serum/plasma doesn t necessarily represent tissue concentrations and elimination characteristics. Drug elimination from edible tissues can behave very differently below and beyond existing data. A tolerance and an MRL are different things. Zero ( no detectable residues is getting smaller and smaller
What happens during drug approval? During the approval process Efficacy Target animal safety Environmental safety Food Safety Toxicity Microbial safety Both of these could be the driver for the Acceptable Daily Intake (ADI). We are going to focus on the toxicity route.
A tolerance comes from First, toxicology studies determine a No Observable Effect Level (NOEL). Depending on the characteristics of the studies, a safety factor is selected. Example: A NOEL of 5 mg/kg per day of the drug is determined in the test species. The maximum safety factor of 1000 is selected in this case. The NOEL of 5 mg/kg divided by 1000 is 0.0005 mg/kg, or 5 µg/kg. This is the Acceptable Daily Intake (ADI)
g, mg, µg, ng, pg? 1 g = 1000 mg = 1,000,000 µg = 1,000,000,000 ng A Picogramis one trillionth of a gram We can pick that much up for some drugs in a ml of plasma or gram of tissue. Nanogramlevels (per gram or ml) are achievable now for many drugs.
Now that we have an ADI we can determine the Safe Concentration in edible tissues. The safe concentration for drug residues represents the amount of drug (parent and metabolites) which can be consumed daily throughout a lifetime.
Safe Concentration The safe concentration for cattle muscle will be calculated from the ADI (5 µg/kg or ppb in this example), the average weight of man at 60kg, and the daily human intake of muscle at 500 g this yields a safe concentration of 600 ppb (ng/g) for muscle (5 x 60 divided by 500).
Converting from muscle to Liver: x food factor of 2 (we only eat about half as much liver as beef) Kidney: x3 Fat: x4 These are based on the assumption we will only eat an entire daily portion of one of these tissues on any given day.
Now that we have a safe concentration The toleranceis the amount of a specific residue, which, when the total residue concentrations are near the safe concentration, will be a consistent percentage of the total residues. Example: The safe concentration (600 ppb) is comprised of A, B, and C components. If A is 50% of the total, the tolerance for A is 300 ppb. Component A is the marker residue, and when it is at 300 ppb, we know that we are at the safe concentration of 600 ppb for total residues in that tissue.
Injection Sites? Injection sites are typically allowed to have a higher concentration than the tolerance in the target residue tissue due to a much lower chance of a consumer repeatedly encountering a residue from consuming that site.
How do we get from a tolerance to a slaughter withdrawal time?
Slaughter Withdrawal Times A residue elimination study is done in the target animal species A target residue tissue is determined as the last organ below tolerance this assures the other edible tissues are below tolerance Statistical analysis is applied to the study data so that when the withdrawal time is reached, only 1 in 1000 animals is likely to still have residues above tolerance in the target residue tissue.
So. There can be legally acceptable concentrations of drugs in edible tissues (except for a carcinogenic parent drug or metabolites) at slaughter IF there is an established tolerance in tissues for that animal species. For drugs without a label and corresponding tolerance in a species (including use class and edible tissue), then any residue detected is violative.
How are residues monitored?
Types of testing
Bob Veal sampling procedure
What are the problems?
DRUG 2005 2006 2007 2008 Total Percent Amikacin 4 2 0 1 7 0.20% Ampicillin 6 10 13 8 37 1.04% Ceftiofur * * * 71 71 1.99% Dihydrostreptomycin 14 10 8 3 35 0.98% Florfenicol 1 0 0 0 1 0.03% Flunixin 121 133 262 233 749 20.99% Furazolidone 1 1 0 0 2 0.06% Gentamicin 77 95 58 50 280 7.85% Kanamycin 2 1 0 0 3 0.08% Lincomycin 0 0 1 0 1 0.03% Slide courtesy of Drs. Deborah Cera and Randy Arbaugh, FDA/CVM
TISSUE RESIDUES IN DAIRY CATTLE - RVIS DRUG 2005 2006 2007 2008 Total Percent Neomycin 22 28 23 21 94 2.63% Oxytetracycline 31 30 21 32 114 3.20% Penicillin 301 358 413 304 1376 38.57% Phenylbutazone 2 0 4 3 9 0.25% Sulfachlorpyridazine 0 1 0 0 1 0.03% Sulfadimethoxine 102 158 159 135 554 15.53% Sulfamethazine 24 33 33 22 112 3.14% Sulfathiazole 1 2 0 0 3 0.08% Tetracycline 16 16 7 15 54 1.51% Tilmicosin 17 27 14 4 62 1.74% Tylosin 1 0 1 1 3 0.08% 743 905 1017 903 3568 * Prior to July 28, 2008 USDA could not quantitate Ceftiofur Slide courtesy of Drs. Deborah Cera and Randy Arbaugh, FDA/CVM
27 An Interactive Database Containing Information Acquired During FDA/State Inspections of Firms Involved/Responsible for Tissue Residue Violations. Attachment C Ensures Consistent Data Collection by both Federal and State Investigators. Attachment C Forms are Entered into TRIMS Slide courtesy of Drs. Deborah Cera and Randy Arbaugh, FDA/CVM
28 Treatment Records Not Maintained Withdrawal Time Not Followed Exceeded Approved Dose Extra Label Use by Laymen Drugs Given or Fed by Mistake Slide courtesy of Drs. Deborah Cera and Randy Arbaugh, FDA/CVM
Reason Drug Used - FY08 Preventive 12% Illness 88% 2/14/2012 Slide courtesy of Drs. Deborah Cera and Randy Arbaugh, FDA/CVM 29
KEY 30 A1- Animal fed colostrum A2- Animal fed medicated feed by mistake A3- Drug given by mistake A4- Failure to maintain animal id and medication records A5- Inadequate animal segregation A6- Failure to follow withdrawal time A7- Feed manufacturing cgmps B1- Vet s prescribed withdrawal time not followed B2- Vet s verbal withdrawal time not followed B3- Animal treated with higher dose B4- Labeled route of administration not followed B5- No withdrawal period prescribed B6- Drug not approved for species B7- Frequency different than labeled B8- Duration of treatment longer than labeled C- Could not Determine D- Drug not same as reported by FSIS E- Told purchaser that animal was medicated and it was later diverted F- All labeled directions followed and documented G. Miscellaneous other causes Slide courtesy of Drs. Deborah Cera and Randy Arbaugh, FDA/CVM
31 Failure to follow withdrawal time Animal treated with higher dose Animal fed colostrum Animal fed medicated feed by mistake Labeled route of administration not followed Drug not approved for species Could not determine Misc. All labeled directions followed and documented Slide courtesy of Drs. Deborah Cera and Randy Arbaugh, FDA/CVM
Slide courtesy of Drs. Deborah Cera and Randy Arbaugh, FDA/CVM
33 160 140 120 100 80 60 40 FY08 20 0 Slide courtesy of Drs. Deborah Cera and Randy Arbaugh, FDA/CVM
Yes 30% No 70% 2/14/2012 Slide courtesy of Drs. Deborah Cera and Randy Arbaugh, FDA/CVM 34
Withdrawal times must be extended in the case of extralabel use But, under absolutely no circumstancesis there justification for shortening a withdrawal period
Things that get us in trouble Just blowing off withdrawal times No records No protocols No training of employees on protocols Extra-label use (ELDU) without the proper guidance Under the AMDUCA regulations, a veterinarian MUST be involved in any ELDU in the form of a VCPR
Extralabel use (ELDU) Whenever a drug is used other than exactly as specified on the label Dose Route Duration Frequency Injection site (location and volume per site) Treatment indication Animal species and use class
Animal Medicinal Drug Use Clarification Act (AMDUCA) The regulations written for this act are what we really need to understand. There is a clear hierarchy of uses in the AMDUCA regulations Use of a labeled product as labeled Use of a food animal-labeled product in an extralabel manner Use of a human or non-food animal veterinary labeled drug Use of a compounded drug
AMDUCA Applies only within the confines of a valid veterinary-client-patient relationship The regulations apply only to products that are approved for use in either animals or humans For example, solvent grade DMSO is not legal to put in a food animal at any time. The animal would be adulterated by using this product.
Confirm it is legal The vets job in ELDU Determine that the use makes sense medically Determine the extended withdrawal time There must be information available to do this or the drug cannot be used in this manner Assure that the animals are correctly identified for observation of the extended withdrawal time Provide the drug or the prescription
Practices that just don t make sense Putting an entire dose of Penicillin G in one spot And what about procaine/benzathine pen G? Putting a drug in another injection site than as labeled Moving ceftiofur crystalline free acid to the neck instead of the ear or base of the ear Giving flunixin meglumine intramuscularly
Practices that just don t make sense Gentamicin There IS a reason why FARAD recommends an 18 month slaughter withdrawal time for this drug. It lights up prolonged kidney residues even when given intramammary Using any drug in an extralabel manner outside the presence of a veterinary-clientpatient relationship (this would be illegal)
Practices that just don t make sense Using compounded products outside of compliance with the AMDUCA regulations There is a compliance policy guideline for compounding. (CPG 608.400) The FDA/CVM DOEShave the authority to regulate compounded products just as they do for approved drugs.
It all comes down to Develop a treatment protocol Case definition Regimen (with a qualified veterinarian) Outcome definitions Animal disposition (animal ID!) Adhere to the protocol Monitor adherence and outcomes Records (and check them before selling an animal)