FOOD ANIMAL RESIDUE AVOIDANCE DATABANK 2023-2024

• Sponsoring Institution: National Institute of Food and Agriculture
• Project Status: COMPLETE
• Funding Source: OTHER GRANTS
• Reporting Frequency: Annual
• Accession No.: 1031335
• Grant No.: 2023-41480-41037
• Cumulative Award Amt.: $810,000.00
• Proposal No.: 2023-06752
• Project Start Date: Sep 1, 2023
• Project End Date: Aug 31, 2024
• Grant Year: 2023
• Program Code: [FARAD]- Food An. Res. Avoidance Database,FARAD

Recipient Organization
NORTH CAROLINA STATE UNIV
(N/A)
RALEIGH,NC 27695

Performing Department
(N/A)

Non Technical Summary
The Food Animal Residue Avoidance Databank (FARAD) program is a chemical food safety program that has been in existence for almost 41 years. This has been a collaborative effort by scientists from five veterinary colleges at North Carolina State University, University of California Davis, University of Florida, Kansas State University, and Virginia Tech Virginia-Maryland. The goal of FARAD is to provide the most updated information resulting in the production of safe foods of animal origin through the prevention and mitigation of violative chemical (drug, pesticide, natural toxins, and environmental contaminant) residues. The program accomplishes this through its objectives which are to identify, extract, assemble, evaluate and distribute reviewed information about residue avoidance and mitigation to persons such as veterinarians, extension agents, and regulatory scientists involved in residue avoidance programs throughout the United States. Each of the FARAD centers has expertise for delivery of the required information which eliminates redundancies and allows for smooth collaboration of collective talents unique to the field of veterinary pharmacokinetics research and related database management. The primary role of FARAD at NCSU is to respond to residue cases in livestock from food animal veterinarians and extension specialist, develop a population pharmacokinetics (PopPK) - Responder interface that takes into account population variance while facilitating its use by FARAD responders on the front lines of residue cases, and to provide research support that attempts to validate estimated withdrawal intervals following extralabel drug use. The latter is the primary reason why FARAD is utilized in residue cases. In addition to the above NC FARAD region will also continue to manage the Response Center with a timely response to cases pertaining to residue avoidance to veterinarians and producers and other stake holders.

Animal Health Component

25%

Research Effort Categories

Basic

50%

Applied

25%

Developmental

25%

Classification

Knowledge Area (KA)	Subject of Investigation (SOI)	Field of Science (FOS)	Percent
308	3260	1180	11%
308	3410	1180	11%
308	3510	1180	14%
308	3210	1180	25%
308	3610	1180	14%
308	3820	1180	14%
308	3310	1180	11%

Knowledge Area
308 - Improved Animal Products (Before Harvest);

Subject Of Investigation
3610 - Sheep, live animal; 3210 - Egg-type chicken, live animal; 3310 - Beef cattle, live animal; 3510 - Swine, live animal; 3260 - Poultry meat; 3820 - Goats, meat, and mohair; 3410 - Dairy cattle, live animal;

Field Of Science
1180 - Pharmacology;

Keywords

drug residues

pharmacokinetics

modeling

Goals / Objectives
The goal of FARAD is to provide the most updated information resulting in the production of safe foods of animal origin through the prevention and mitigation of violative chemical (drug, pesticide, natural toxins, and environmental contaminant) residues. The program accomplishes this through its objectives which are to identify, extract, assemble, evaluate and distribute reviewed information about residue avoidance and mitigation to persons such as veterinarians, extension agents, and regulatory scientists involved in residue avoidance programs throughout the United States. The primary role of FARAD at NCSU is to respond to residue cases in livestock from food animal veterinarians and extension specialist, develop a population pharmacokinetics (PopPK) - Responder interface that takes into account population variance while facilitating its use by FARAD responders on the front lines of residue cases, and to provide research support that attempts to validate estimated withdrawal intervals following extralabel drug use. The latter is the primary reason why FARAD is utilized in residue cases. In addition to the above NC FARAD region will also continue to manage the Response Center with a timely response to cases pertaining to residue avoidance to veterinarians and producers and other stake holders.

Project Methods
The regional center at NCSU will continue to support the essential tasks of the national FARAD program outlined below, provide pharmacokinetic services to all FARAD sites, and continue developing pharmacokinetic model tools that allow FARAD responders to fully utilize published studies to avoid meat, egg, and milk violative residues in food animals. The primary focus areas of the NC FARAD component for 2023 - 2024 are as follows: (1) collaborate with KSU, UC Davis, Virginia Tech, and University of Florida, to validate (via in vivo studies) many of our computational estimates of a safe withdrawalintervals; (2) strengthen the response team by recruiting graduate students at NCSU-CVM and working closely Dr. Jennifer Davis' team at Virginia Tech. and Dr. Lisa Tell's team at UC Davis to provide drug and chemical residue management expertise to veterinarians by answering telephone and internet inquiries; (3) continue to implement an interface between developed PopPK models and residue cases for those PopPK models already developed by FARAD over the last 20 years. The latter will continue to be tasked to our PhD graduate student in pharmacometrics, Farha Ferdous (M.S) and Dr. Rob DeWoskin (Ph.D, DABT) to provide QA/QC of all FARAD models. Dr. Kristin Messenger will continue to provide her expertise in PopPk and develop PK/PD models in livestock with our graduate students.Pharmacokinetics Trials One specific focus area for 2023-2024 will be to continue our work with Dr. Derek Foster (DVM, DACVIM) and Dr. Jennifer Halleran (DVM, PhD, DACVIM). They have brought their expertise in food animal internal medicine and antimicrobial resistance (AMR) in cattle and attempting to understand drug residue deposition in various tissue compartments and how it is related to AMR. There is the question of whether drug residue withdrawal times have any effect on emerging AMR. Our team will continue to assess drug residues (e.g., fluralaner) in laying hens as backyard poultry continues to be about 30% of calls that FARAD receives and we have very limited data to help poultry farmers and veterinarians. Our ruminant team will also be completing our goat residue trials with flunixin for which there is no data and also continue other ruminant projects related to Dr. Foster's antimicrobials and Dr. Halleran's work with macrolides in cattle. Our team will be conducting poultry, swine, and ruminant trials and to validate physiologically-based PK (PBPK) models and mixed effect (PopPK) models developed by our team and several poultry trial.Respond to drug and chemical residue cases: The NCSU FARAD Regional Access Center will continue in collaboration with UC-Davis FARAD Regional Access Center and response center at Virginia Tech to answer residue avoidance. This service at NC FARAD will be led by our new hire, Dr. Danielle Mzyk, DVM, PhD as a Clinical Veterinarian in food animal medicine, and also our postdocoral associate, Dr. Hiroko Enomoto who has been developing significant PK experience in our laboratory and she will be working very closely with Dr. Baynes his graduate students and the other regional response centers. The strengthening of the response team at NCSU will greatly facilitate literature retrieval and the accuracy and timeliness of NCSU's response to as many as 70 cases a week. We will continue to collaborate on writing timely FARAD Digests that focus on the management of the more common drug residue scenarios facing food animal veterinarians. We will continue to collaborate in outreach programs to producer groups and veterinary specialty groups such as AVMA, AABP, AAVPT, and US Codex. Dr. Baynes represents FARAD and AAVPT in bimonthly US Codex delegation discussions. Dr. Foster is an active member of AABP and has provided key feedback to FARAD from bovine veterinarians regarding the quality of FARAD service provided to veterinarians.Implementation of a PopPK Responders Interface: FARAD has developed numerous PopPK models over the last 20 years. Several of these models have part been validated for the most part and therefore robust enough to be implemented to help answer drug residue questions fielded by our FARAD responders. We intend to continue building an interface between these models and questions presented to our responders so that our recommended withdrawal intervals are population-based and more reliable than using traditional PK parameters and methods that are based on average parameter values and does not take into account population variance. In terms of developing pharmacokinetic model tools, our long-term goal is to develop a web-based interactive tool that allows FARAD responders to easily calculate drug withdrawal intervals after extralabel use of different drugs in different food animal species. To achieve this long-term goal and build upon our earlier work we plan to develop popPK models describing withdrawal intervals for common drugs in common species.

Progress 09/01/23 to 08/31/24

Outputs
Target Audience:Food animal veterinarians, extension specialists, livestock farmers, and animal scientist in the management of drug and chemical residues in livestock animals. Dr. Baynes also represents FARAD as part the US delegation to Codex and participates in bi-monthly meetings. Dr. Foster sits on several AABP committees and has represented FARAD at AABP and by managing the FARAD booth at AABP meetings every September. Changes/Problems:NC FARAD successfully recruited a Clinical Veterinarian, Dr. Danielle Mzyk, in January 2023 to help manage the increased number of FARAD calls. We also added Dr. Desirae Hanna as a part time responder to help us with the increased case volume. We have been able to recruit Earl Ford, who is conducting his PhD research in our laboratory with the aim of better estimating meat and milk residues in dairy cattle exposed to antidote medication as well pain medication in cattle. What opportunities for training and professional development has the project provided?Graduate students: During the reporting periodNC FARAD supported graduate students and apostdoc. Ranee Miller has been working milk residue depletion in cows treated during off period and Farha Sheela has been woking on developing PopPK Modeling of drug residues in cattles. Dr. Hiroko Enomoto joined the NC FARAD team in April 2021 as a postdoc to work on the sample analysis of several livestock drugs and PK modeling critical to the NC FARAD mission. The latter is already a first author or co-author on several publications (poultry residues) funded by this grant. A new graduate student from the NCSU Toxicology program joined the team in Jan 2023 and is working on a project pertaining to drug resides following the use of antidotal medication in cattle. This was a request from AABP as their veterinarians see that as a need. Undergraduate students: Several undergraduate students and veterinary students benefited from working in the residue laboratory during the summer and learnt how pharmacokinetic studies are conducted. One DVM student has gone into mixed practice in NC. One DVM student completed a summer 2024 project looking at PK of transdermal flunixin in wool and short haired sheep and is about the submit a paper for peer-reviewed publication this academic year. How have the results been disseminated to communities of interest?The results from this FARAD project have been disseminated in peer-review publications (see publications and posters and oral presentations) as well at relevant livestock meetings and CE courses. What do you plan to do during the next reporting period to accomplish the goals? Nothing Reported

Impacts
What was accomplished under these goals? Major Goals of the project The program goals of FARAD is to provide the most updated information that result in the production of safe foods of animal origin through the prevention and mitigation of violative chemical (drug, pesticide, natural toxins, and environmental contaminant) residues in food animal products. The aim of this program is to maintain updated information on drug residues and related federal regulations as well as to help veterinarians and producers manage drug or chemical exposures in livestock that could result in violative residues in animal-derived food. This project therefore has an outreach component as well as research and training component. North Carolina State University FARAD continued to provide responses to residue avoidance inquiries. This was shared by the University of California, Virginia Tech University, and North Carolina State University FARAD staff. FARAD telephone and e-mail inquiries were answered on a weekly, rotating basis between the three sites. These services at NC FARAD were directed by the PI, Dr. Ronald Baynes, and his team of responders which included clinicians and veterinarians (graduate students, postdocs). During the last year we also added, Dr. Deserae Hanna (PharmD) as a part time responder on FARAD calls. All personnel were also actively involved in teaching drug residue avoidance principles to veterinary students, interns, residents, and graduate students. The NC FARAD component accomplished the following during the project period: Outreach activities: Our NC FARAD office provided technical expertise via phone calls (1-800-USFARAD) or via the internet and shares with responsibility with weekly rotations between NC FARAD, UC Davis, and Virginia Tech. We do not have the 2024 data, but for 2023 alone, the regional access centers answered 5,825 specific inquiries through emergency telephone calls or the online submission portal (entailing multiple drugs/contaminants) that directly involved approximately 5.8 million animals. This was a significant 33% increase compared to 2022. Our FARAD responders at all three sites essentially screen the residues calls and the PIs supervise the responses. In very difficult cases (e.g., limited data set; possible carcinogens), all PIs across all 5 sites are involved as well as all responders. The table below is a summary of the growth of usage of several components of the FARAD program in the last two years. This often involved advising veterinarians and farmers on the best means to handle a drug residue case. FARAD may field as many as 70 calls a week and several times in 2023 we fielded slightly more than 100 calls per week. This means that sometimes as many as 15 - 20 cases per day and any given case may involve more than one livestock species or more than one drug or chemical exposure. Many of these cases were resolved within 24-48 hours, but complex chemical contaminant cases required more research and consultation and have taken close to 1 week to resolve. As backyard farming continues to grow in the US, (especially poultry in recent years), we see an increasing pattern of requests for guidance in these situations. NC FARAD faculty have made presentations as CE courses and manages educational booths on food animal residues and mitigation at the annual American Association of Bovine Practitioners (AABP) meetings amongst other meetings and workshops. In recent years at the request form AABP leadership on contentious issues. User access to FARAD Resources during the previous year USAGE REPORT PERIOD MEASURE 2023 Inquiries to Regional Access Centers (hotline plus email) 5825 (+33%) Visit to 234,594 (+105%) www.farad.org VetGRAM Page 130,457 Visits In this submission, all data are adjusted to reflect the calendar year. Data on user access to FARAD resources are shown in the table above. Research activities: Our NC FARAD office has been conducting drug residue research that has focused on: (1) Development of PK models in cattle, poultry, and swine, (2) Drug residues in poultry eggs and meat, (3) Drug residues in pigs associated with extralabel drug use of ponazuril, (4) flunixin drug residues in meat goats, and (5) milk residues studies in dairy cattle treated at different stages of the dry off period. These involved a significant amount of effort with recruitment of animals and space to conduct the residue studies as well as significant analytical method development for the analysis of these drugs in various tissues including milk and eggs. The data from our work adds to our database needs to help address the more pressing drug residue issues and challenges facing our food animal veterinarians and livestock producers. These research activities have also resulted in several publications and abstract and oral presentations at national meetings (e.g., AABP, AASV) and in March 2024 conducted a special symposium on food animal residue research activities at the Annual Society of Toxicology meeting in Salt Lake City, Utah. Our FARAD program continues to be a first stop on residues questions and drug residue policy issues from such organizations such as the AABP and AASV. NC FARAD continues to be a resource for livestock producers such as Smithfield and House of Raeford in NC.

Publications

• Type: Peer Reviewed Journal Articles Status: Published Year Published: 2023 Citation: Gonzalez-Morales MA, Thomson A, Yeatts J, Enomoto H, Haija A, Santangelo RG, Petritz OA, Crespo R, Schal C, Baynes R. Pharmacokinetics of fluralaner as a systemic drug to control infestations of the common bed bug, Cimex lectularius, in poultry facilities. Parasit Vectors 16(1):333. doi: 10.1186/s13071-023-05962-3, 2023.
• Type: Peer Reviewed Journal Articles Status: Published Year Published: 2023 Citation: Petritz OA, Enomoto H, Meyer EG, Thomson A, Baynes RE, and Flammer K. Pharmacokinetics and safety of sulfamethoxazole-trimethoprim after oral administration of single and multiple doses to Rhode Island Red chickens (Gallus gallus domesticus). J Avi Med Surg 37(1):1-12, 2023. doi: 10.1647/22-00020.
• Type: Peer Reviewed Journal Articles Status: Published Year Published: 2023 Citation: Mzyk DA, Giles CB. Baynes RE, Smith GW. Milk residues following multiple doses of meloxicam and gabapentin in lactating dairy cattle. J Am Vet Med Assoc 261(12):1873-1879. doi: 10.2460/javma.23.06.0329, 2023. [PMID: 37734723]
• Type: Peer Reviewed Journal Articles Status: Published Year Published: 2023 Citation: Zad N, Tell LA, Ampadi Ramachandran R, Xu X, Riviere JE, Baynes R, Lin Z, Maunsell F, Davis J, Jaberi-Douraki M. Development of machine learning algorithms to estimate maximum residue limits for veterinary medicines. Food Chem Toxicol 179:113920. doi: 10.1016/j.fct.2023.113920, 2023. [PMID: 37506867].
• Type: Peer Reviewed Journal Articles Status: Published Year Published: 2023 Citation: Chou WC, Tel LA, Baynes RE, Davis JL, Cheng YH, Maunsell FP, Riviere JE, Lin Z. Development and application of an interactive generic physiologically based pharmacokinetic (igPBPK) model for adult beef cattle and lactating dairy cows to estimate tissue distrubtion and edible tissue and milk withdrawal intervals for per- and polyfluoroalkyl substances (PFAS). Food Chem Toxicol 181:114062. doi: 10.1016/j.fct.2023.114062, 2023. [PMID: 37769896].
• Type: Peer Reviewed Journal Articles Status: Published Year Published: 2024 Citation: Elliot BA, Enomoto H, Petritz OA, Crespo R, Yeatts J, Fricke I, Singleton A, Thomson A, Baynes RE. Pharmacokinetics of intravenously and trans-dermally administered fluralaner in healthy laying shaver hens: fluralaner in chickens. Poult Sci 103(3):103362. doi: 10.1016/j.psj.2023.103362, 2024. [PMID: 38218115]
• Type: Peer Reviewed Journal Articles Status: Published Year Published: 2024 Citation: Enomoto H, Elliot BA, Petritz OA, Crespo R, Yeatts J, Sheela FF, Fricke I, Singleton A, Thomson A, Baynes RE. Residue, distribution and depletion of fluralaner in egg following a single intravenous and transdermal administration in healthy shaver hens: fluralaner residue in egg. Poult Sci 103(7):103843. doi: 10.1016/j.psj.2024.103843, 2024.
• Type: Peer Reviewed Journal Articles Status: Published Year Published: 2023 Citation: Giles CB, Ferdous F, Halleran JL, Yeatts JL, Baynes RE, Mzyk DA. Flunixin meglumine tissue residues after intravenous administration in goats. Front Vet Sci 10:1341779. doi: 10.3389/fvets.2023.1341779. eCollection 2023, 2023 [PMID: 38264467]
• Type: Peer Reviewed Journal Articles Status: Published Year Published: 2024 Citation: Wiloch EE, Enomoto H, Smith L, Baynes RE, Messenger KM. Pharmacokinetics of intranasal and intramuscular flunixin in healthy grower pigs. J Vet Pharmacol Ther 47(2):150-153. doi: 10.1111/jvp.13426, 2024. [PMID: 38204379]
• Type: Conference Papers and Presentations Status: Other Year Published: 2024 Citation: Development and applications of PBPK models to predict tissue residues and withdrawal times of drugs in food-producing animals to support food safety assessment (Zhoumeng Lin). Part of the Workshop entitled Use of PBPK and Novel Pharmacokinetic Approaches for the Quantitative Prediction of Tissue Residue and Withdrawal Times for Human Food Safety Assessment. (Chairs: Ronald Baynes and Zhoumeng Lin) The 63rd Annual Meeting of Society of Toxicology, Salt Lake City, UT. The Toxicologist, Supplement to Toxicological Sciences, 198, (S1), p. 15, abstract #: 1055. (March 10-14, 2024)
• Type: Conference Papers and Presentations Status: Other Year Published: 2024 Citation: The Pharmacokinetics of Methylene Blue in Cattle. (Earl Ford); The 63rd Annual Meeting of Society of Toxicology, Salt Lake City, UT. The Toxicologist, Supplement to Toxicological Sciences, 198, (S1), abstract/poster board #: 4513/P3342003. (March 10-14, 2024)
• Type: Conference Papers and Presentations Status: Other Year Published: 2024 Citation: Quantifying trade-offs between therapeutic efficacy and resistance dissemination for enrofloxacin dose regimens in cattle. (Chandra Deb L, Foster DM. Lanzas C). Conference of Research Workers in Animal Diseases. Jan 2024. Chicago, IL.
• Type: Conference Papers and Presentations Status: Other Year Published: 2024 Citation: Characterization of the oral pharmacokinetics of tylosin and its effect on the rumen microbiome. (Halleran JL, Dillenbeck L, Mzyk DA, Foster DM ). Conference of Research Workers in Animal Diseases. Jan 2024. Chicago, IL.
• Type: Conference Papers and Presentations Status: Other Year Published: 2024 Citation: Establishing Withdrawal Periods and Tolerances or Maximum Residue Levels in the US and International Jurisdictions (Ronald Baynes). Part of the Workshop entitled Use of PBPK and Novel Pharmacokinetic Approaches for the Quantitative Prediction of Tissue Residue and Withdrawal Times for Human Food Safety Assessment. (Chairs: Ronald Baynes and Zhoumeng Lin) The 63rd Annual Meeting of Society of Toxicology, Salt Lake City, UT. The Toxicologist, Supplement to Toxicological Sciences, 198, (S1), p. 15, abstract #: 1052. (March 10-14, 2024)
• Type: Conference Papers and Presentations Status: Other Year Published: 2023 Citation: An introduction to FARAD (Food Animal Residue Avoidance Databank) (Danielle Mzyk) . University of Georgia Poultry Department. August, 2023, Athens, GA.
• Type: Conference Papers and Presentations Status: Other Year Published: 2023 Citation: Extra label drug use and the role of FARAD in preventing violative residues. (Danielle Mzyk) October 2023, University of Arizona, College of Veterinary Medicine, October, 2023. Tucson, AR.
• Type: Conference Papers and Presentations Status: Other Year Published: 2024 Citation: Impact of florfenicol dosing regimen on the phenotypic and genotypic resistance of enteric bacteria in steers. Conference of ResearchWorkers in Animal Diseases. (Halleran JL, Neumann LM, Mzyk DA, Foster DM). Jan 2024. Chicago, IL.
• Type: Conference Papers and Presentations Status: Other Year Published: 2023 Citation: Pharmacokinetics of oral phenazopyridine in goats with obstructive urolithiasis. (Mitman SL, Camacho BE, Neumann LM, Schwartz M, Mzyk DA, Baynes R, Foster DM, Halleran JL.) American Association of Bovine Practitioners Conference. Sept 2023. Milwaukee, WI.
• Type: Conference Papers and Presentations Status: Other Year Published: 2023 Citation: Clinical pharmacology and drug residues in calves and small ruminants, (Danielle Mzyk), North Carolina Veterinary Conference, November, 2023, Raleigh, NC.
• Type: Conference Papers and Presentations Status: Other Year Published: 2024 Citation: Estimating Maximum Residue Limits for Veterinary Medicines Using Machine Learning Algorithms; The 63rd Annual Meeting of Society of Toxicology, Salt Lake City, UT. The Toxicologist, Supplement to Toxicological Sciences, 198, (S1), p. 14, abstract #: 1053. (March 10-14, 2024)
• Type: Conference Papers and Presentations Status: Other Year Published: 2024 Citation: Advancing Food Safety: Predicting Maximum-Residue-Limits for Veterinary Medicines using AI/ML. Author(s): Remya Ampadi Ramachandran, Nader Zad, Lisa A. Tell, Xuan Xu, Jim E. Riviere, Ronald Baynes, Zhoumeng Lin, Fiona Maunsell, Jennifer Davis, Majid Jaberi-Douraki. Poster Session, Nexus Informatics Conference, Kansas City, April 25-26, 2024.