FOOD ANIMAL RESIDUE AVOIDANCE DATABANK (FARAD)

• Sponsoring Institution: National Institute of Food and Agriculture
• Project Status: COMPLETE
• Funding Source: OTHER GRANTS
• Reporting Frequency: Annual
• Accession No.: 1006747
• Grant No.: 2015-41480-23972
• Cumulative Award Amt.: $396,000.00
• Proposal No.: 2015-08171
• Project Start Date: Sep 1, 2015
• Project End Date: Aug 31, 2018
• Grant Year: 2015
• Program Code: [FARAD]- Food An. Res. Avoidance Database,FARAD

Project Director
Lin, Z.

Recipient Organization
KANSAS STATE UNIV
(N/A)
MANHATTAN,KS 66506

Performing Department
Anatomy and Physiology

Non Technical Summary
The Food Animal Residue Avoidance and Depletion (FARAD) program which maintains the Food Animal Residue Avoidance Databank is a chemical food safety program that has been in existence for over 33 years and has been a collaborative effort by scientists from as many as four veterinary colleges at Kansas State University, North Carolina State University, University of California Davis, and the University of Florida. The program goal 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 program accomplishes this through its objectives which are to identify, extract, assemble, evaluate and distribute reviewed information about residue avoidance and mitigation to people involved in residue avoidance programs throughout the United States. In many cases this data does not exist, requiring extensive computational modeling be developed to provide valid estimates for ensuring safe food. FARAD this year will also continue to develop a global system to insure safe imports into the US and facilitate export of residue-free meat, milk and eggs. Each of the four FARAD centers has expertise for generation and 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.

Animal Health Component

75%

Research Effort Categories

Basic

25%

Applied

75%

Developmental

(N/A)

Classification

Knowledge Area (KA)	Subject of Investigation (SOI)	Field of Science (FOS)	Percent
307	5010	3030	50%
502	5010	1060	25%
511	5010	3030	25%

Knowledge Area
511 - New and Improved Non-Food Products and Processes; 307 - Animal Management Systems; 502 - New and Improved Food Products;

Subject Of Investigation
5010 - Food;

Field Of Science
1060 - Biology (whole systems); 3030 - Information and communication;

Keywords

chemical food safety

food animal

pharmacology

residues

Goals / Objectives
The elemental goal of FARAD is the production of safe foods of animal origin through the prevention and mitigation of volatile chemical (drug, pesticide, natural toxins, and environmental contaminant) residues in food animal products. FARAD's objectives are to identify, extract, assemble, evaluate and distribute reviewed information about residue avoidance and mitigation to people involved in residue avoidance programs throughout the United States. The types of information available through FARAD include basic veterinary drug registration information, withdrawal times, indications for use, as well as complex technical information about the pharmacokinetics and toxicokinetics of drugs and chemicals in food animals.

Project Methods
The objective of the four collaborating universities is to continue the development and delivery of FARAD, and to utilize current technologies to make changes in FARAD which will improve its usefulness and utility as a decision support system. The five primary tasks include:1. Extraction and validation of data for incorporation into the system and support for FARAD's approved drug databases for publication in electronic format (VetGRAM) for internet delivery. This includes extraction of relevant data from foreign drug compendia and gFARAD partners.2. Operation of the Regional Access Centers (RAC's) at KSU, NCSU and UCD for provision of residue avoidance information, with access through the toll-free hotline and e-mail.3. Data entry, pharmacokinetic analysis, maintenance, and distribution of the FARAD files.4. Preparation of FARAD Digests for publication in the Journal of the AVMA, Newsletters, FARAD Fact Sheets when appropriate for rapid dissemination of information in an ongoing crisis, and other publications for distribution.5. Develop and validate methods to allow extrapolative techniques to be used in providing advice in situations where no direct data exists, the norm for mitigating environmental contaminant exposures.The breakdown of functions for the national program are as follows:Kansas State University (KSU) -Coordinate national program, develop pharmacokinetic modeling approaches and provide pharmacokinetic support to FARAD components, and on a rotating schedule with NCSU and UCD, provide responses to emergency queries from the FARAD Hotline.The University of California (UCD) - maintains the pharmacokinetic, bibliographic and call center databases and web-based access to the kinetic and bibliographic citation files. On a rotating basis with NCSU and KSU, UCD provides responses to drug and contaminant residue questions.The University of Florida (UFL)- Collects and enters data for the US Approved Animal Drugs Database (US-AADD), maintains internet websites for FARAD, creates and supports platforms for mobile devices to access the Veterinarian's Guide to Residue Avoidance Management (VetGRAM) and other mobile-friendly applications, and distributes electronic alerts and updates via email, Twitter and other electronic formats.North Carolina State University (NCSU)- On a rotating schedule with UCD and KSU, provides responses to emergency telephone calls from the FARAD hotline.FARAD functions through the collection of a variety of data related to the depletion of drugs and chemicals in animal tissues and the application of these data in formulating recommendations to its clients to avoid or mitigate residues. This process can involve the use of simple mathematical extrapolations or novel complicated algorithms where no readily applicable data exists to predict chemical depletion. FARAD personnel at UCD search the scientific literature for information about the elimination of chemicals from food producing animals, extract these data when relevant, and enter it into a databank for easy retrieval. Because many factors may affect how fast an animal eliminates a residue; information about diet, age, sex, breed, and disease are collected. The databank allows information to be rapidly brought to bear on accidental residue problems arising from exposure to environmental contaminants or to advise veterinarians on avoiding residues from extralabel drug therapy.The initial data that FARAD collects is associated with FDA's drug approval process collected and maintained at UF. Those data include details of submissions on drug toxicity [target species as well as human] and depletion data used to determine label withdrawal times in the target species. These data are available on FARAD's web-based interactive database the Veterinarian's Guide to Residue Avoidance Management [VetGRAM] found at www.FARAD.org and now are available in mobile platforms. These FARAD products provide information about drugs that are approved for treating animal diseases, and the associated withholding times for milk, eggs, honey and preslaughter withdrawal times for meat, as well as giving a basis to FARAD personnel for possible extrapolation for extralabel doses and species. When this information is not sufficient, direct access to FARAD experts is available through the FARAD Regional Access Centers at KSU, NCSU and UCD. FARAD thus provides multilayered service to those persons most critical to the production of safe foods of animal origin. FARAD is readily accessible through websites, e-mail, mobile applications and a toll-free telephone hotline, as well as in specific residue-avoidance publications. FARAD provides this guidance through use of its databank by specially trained professional staff to provide information on prevention and mitigation of volatile chemical residues and supplies recommended withdrawal intervals to allow safe extralabel use of drugs in food animals under AMDUCA guidelines based on sound principles of residue avoidance. FARAD is the unique provider of such services.The development of pharmacokinetic strategies to link the chemical depletion data from the literature to the drug safety data from the drug approvals or regulatory authorities are conducted at KSU. The goal is to provide the best estimate of withdrawal time possible for the extra-label drug use contaminant scenario at hand. Since residue data continues to be published daily in journals and regulatory reports, maintenance and addition of new data are essential to accurate advice, FARAD needs assured and uninterrupted funding to be able to offer these services.FARAD has maintained a toll-free number since 1996: 1-888-US-FARAD to respond to specific inquiries for assistance. Over the past 16 years, with encouragement from the American Veterinary Medical Association (AVMA), FARAD has produced the FARAD Digest series for the Journal of the AVMA. These digests provide well-documented information about extralabel drug withdrawal intervals. FARAD is officially allied with other organizations such as the Centre for Applied Biosciences International's (CABI) Animal Health and Production Compendium since 2003 where there are files for inclusion in the various issues of their compendium. We convened a scoping workshop to explore a FARAD/CABI global veterinary drug compendium three summers ago using pass though funds from FDA to NIFA for this purpose.

Progress 09/01/15 to 08/31/18

Outputs
Target Audience:FARAD's immediate clients are practicing veterinarians, regulators, extension officers, producers, and researchers, but it ultimately protects the food consuming public and contributes to human Public Health by equipping these professionals with the best science available. Changes/Problems:There have been considerable changes in the FARAD component as Kansas State University (KSU) throughout the report period. First, Dr. Jim Riviere retired from Kansas State University in May 2017. At that time, Dr. Ronette Gehring had taken over as PI to ensure that full operations could continue seamlessly. However, Dr. Gehring accepted an offer of full professor and chair at the University of Utrecht and left KSU at the end of September, 2017. As a result, we needed to transfer certain functions (databases and applications developed at KSU, as well as analyses of samples collected during a collaborative research project) to FARAD centers at NCSU and UC Davis to ensure continued delivery of outcomes given in the proposal. After Dr. Gehring left, Dr Zhoumeng Lin took over as contact PI of this award at KSU. The specific aims and goals of the proposal were adjusted to fit within Dr. Lin's expertise, which is physiologically-based pharmacokinetic modeling in support of FARAD's mission to provide science based withdrawal interval recommendations. The proposed work has been completed and the publications listed above document the accomplishments and the productivity of the FARAD team at KSU. What opportunities for training and professional development has the project provided?This project directly supported one PhD graduate student, and partially supported three post-doctoral fellows. How have the results been disseminated to communities of interest?See data above on call center and internet access which is the primary route for information dissemination for FARAD. We also published our research in peer-reviewed journals (see the Products page). What do you plan to do during the next reporting period to accomplish the goals? Nothing Reported

Impacts
What was accomplished under these goals? The overall use of FARAD program services has a remarkable increase throughout the past five years in terms of both the number of residue-related questions received via our telephone hotline and internet-based portal as well as the number of visitors to our information resources on the internet (www.farad.org) and mobile platforms. FARAD has continued to operate its telephone hot-line and online access systems throughout the past year, which produced continued growth in the number of calls compared to the previous year. During 2017, the regional access centers answered over 3,366 specific inquiries (entailing multiple drugs/contaminants) that directly involved approximately 9.5 million animals. Given the amount of list-serve sharing of FARAD's answers, these calls most likely indirectly impacted another set of animals, which are unfortunately unquantifiable. The majority of these inquiries were submitted via the world-wide web and remain focused on small production poultry (34%) followed by dairy and beef cattle (26%), then small ruminants (24%), swine (11%) and rabbits (1%). Depending on species, each request may impact either a single animal or large herds or flocks. Situations leading to concerns about violative residues, ranged from cases involving intentional extralabel drug use for therapeutic purposes to situations involving accidental or unavoidable exposures associated with environmental accidents. In addition to specific cases that were submitted via the hot-line, users sought general information on drug and residue avoidance. The reasons for calls are very diverse and range from "ordinary requests" for drug withdrawal recommendations (related to extra-label drug use or accidental drug overdoses) to "extraordinary requests", which include pesticide and contaminant exposures. During 2017, there were 65,046 visitors to the FARAD website (daily average of 178), which represents a net increase of 6.8% over the previous year. While 53,365 visitors (82% of all visitors) originated from IP addresses located within the United States, visits were recorded from 171 separate countries, a slight increase over the previous year. In addition to the United States, other countries included among the top ten total visitors (high to low) were Canada, India, Taiwan, United Kingdom, Australia, Germany, China, Philippines and Mexico. The total number of page visits on www.farad.org remained relatively unchanged from the previous year at 317,134 (up 9.6%) total page visits. One noteworthy change during 2017 was the significant rebound in the number of total visits to VetGRAM, which increased to 107,593 page views following a sharp decline in the previous year. Although we had proposed that the sharp decline in VetGRAM use during 2016 might possibly be associated with increased use of free mobile phone apps, the most recent usage data reveal a return to a continued high demand for the internet-based VetGRAM platform (~ 295 page visits per day). During the past year, new installs of our free VetGRAM apps continued albeit at reduced levels compared to the previous year for both Android phones (318 new downloads) and the iOS-based app for iPhones (106 new downloads). Other highly viewed pages on the FARAD website included the Withdrawal Interval (WDI) Recommendation Lookup, the Veterinary Feed Directive pages, the Withdrawal Date Calculator, the Restricted and Prohibited Drugs page and Extra-Label Drug Use information pages. The primary focus of KSU's work was to answer FARAD calls every third week, and develop physiologically-based pharmacokinetic and population pharmacokinetic models for selected drugs to predict tissue and milk residues in target populations. KSU also provided pharmacokinetic analysis services for all FARAD collaborators. The publications listed above document this productivity. Another focus area was to formalize the theoretical underpinnings of our pharmacokinetic models and algorithms through rigorous review and publication in the scientific literature . Finally, a full-time database developer was hired to continue work on the global database of veterinary products approved for food-producing animals.

Publications

• Type: Journal Articles Status: Published Year Published: 2015 Citation: Marmulak T, Tell LA, Gehring R, Baynes RE, Vickroy TW, Riviere JE. Egg residue considerations during the treatment of backyard poultry. J Am Vet Med Assoc. 247:12: 1388-1395, 2015.
• Type: Journal Articles Status: Published Year Published: 2015 Citation: Shelver WL, Smith DJ, Tell LA, Baynes RE, Schroeder JW, Riviere JE. Screening and confirmatory analyses of flunixin in tissues and bodily fluids after intravenous or intramuscular administration to cull dairy cows with or without lipopolysaccharide challenge. J Agr Food Chem. 64: 1: 336-345, 2015.
• Type: Journal Articles Status: Published Year Published: 2016 Citation: Baynes RE, Dedonder K, Kissell L, Mzyk D, Marmulak T, Smith G, Tell L, Gehring R, Davis J, Riviere JE. Health concerns and management of select veterinary drug residues. Food Chem Tox. 88:112-122, 2016.
• Type: Journal Articles Status: Published Year Published: 2016 Citation: Lin Z, Gehring R, Mochel JP, Lav� T, Riviere JE. Mathematical modeling and simulation in animal health - Part II: principles, methods, applications, and value of physiologically based pharmacokinetic modeling in veterinary medicine and food safety assessment. J Vet Pharmacol Therap. 39:421-438, 2016. [PMID: 27086878]
• Type: Journal Articles Status: Published Year Published: 2016 Citation: DeDonder KD, Gehring R, Riviere JE, Baynes RE, Tell LA, Vickroy TW. Residue concerns following exposure of livestock to oil and petroleum products. J Am Vet Med Assoc. 248: 2: 145-146, 2016.
• Type: Journal Articles Status: Published Year Published: 2016 Citation: DeDonder KD, Gehring R, Tell LA, Riviere JE. Protocol for diversion of confirmed positive bulk raw milk tankers to calf ranches - A review of the Pharmacokinetics of tetracyclines and sulfonamides in veal calves. Anim Health Res Rev, 17(2):127-136, 2016. [PMID:27534578]
• Type: Journal Articles Status: Published Year Published: 2016 Citation: Lin Z, Cuneo M, Rowe JD, Li M, Tell LA, Allison S, Carlson J, Riviere JE, Gehring R. "Estimation of tulathromycin depletion in plasma and milk after subcutaneous injection in lactating goats using a nonlinear mixed-effects pharmacokinetic modeling approach. BMC Vet Res. 12: 1: 258, 2016.
• Type: Journal Articles Status: Published Year Published: 2016 Citation: Lin Z, Vahl CI, Riviere JE. Human food safety implications of variation in food animal drug metabolism. Scientific Reports. 6, 27907, 2016.
• Type: Journal Articles Status: Published Year Published: 2016 Citation: Kissell LW, Brinson PD, Gehring R, Tell LA, Wetzlich SE, Baynes RE, Riviere JE, Smith GW. Pharmacokinetics and tissue elimination of flunixin in veal calves. Am J Vet Res. 77: 6: 634-640, 2016.
• Type: Journal Articles Status: Published Year Published: 2017 Citation: Riviere JE, Tell LA, Baynes RE, Vickroy TW, Gehring R. Guide to FARAD resources: historical and future perspectives. J Am Vet Med Assoc. 250:10: 1131-1139, 2017.
• Type: Journal Articles Status: Published Year Published: 2017 Citation: Mzyk DA, Gehring R, Tell LA, Vickroy TW, Riviere JE, Ragan G, Baynes RE, Smith GW. "Considerations for extralabel drug use in calves." J Am Vet Med Assoc. 250: 11: 1275-1282, 2017.
• Type: Journal Articles Status: Published Year Published: 2017 Citation: Li M, Gehring R, Riviere JE, Lin Z. Development and application of a population physiologically based pharmacokinetic model for penicillin G in swine and cattle for food safety assessment. Food Chem Tox, 107:74-87, 2017. [PMID: 28627373]
• Type: Journal Articles Status: Published Year Published: 2017 Citation: Lin Z, Jaberi-Douraki M, He C, Jin S, Yang RSH, Fisher JW, Riviere JE. Performance assessment and translation of physiologically based pharmacokinetic models from acslX to Berkeley Madonna, MATLAB, and R language: oxytetracycline and gold nanoparticles as case examples. Tox Sci. 158:23-35, 2017. [PMID: 28402537]
• Type: Journal Articles Status: Published Year Published: 2018 Citation: Udiani O, Mason S, Smith G, Mzyk D, Gehring R, Tell L, Riviere JE, Baynes RE. Automation and Applications of the Tolerance Limit Method in Estimating Meat Withdrawal Periods for Veterinary Drugs. Comput Electron Agric 146: 125-135, 2018.
• Type: Journal Articles Status: Published Year Published: 2018 Citation: Stafford EG, Tell LA, Lin Z, Davis J, Vickroy TW, Riviere JE, Baynes RE. (2018). FARAD Digest: Consequences of fipronil exposure in egg-laying hens. J. Am. Vet. Med. Assoc. 253(1):57-60, 2018. [PMID: 29911954]
• Type: Journal Articles Status: Published Year Published: 2018 Citation: Gorden PJ, Burchard M, Ydstie JA, Kleinhenz MD, Wulf LW, Rajewski SJ, Wang C, Gehring R, Mochel JP, Coetzee JF. Comparison of milk and plasma pharmacokinetics of meloxicam in postpartum versus mid-lactation Holstein cows. J Vet Pharmacol Ther. 41(3):463-468, 2018. [PMID: 29430684]
• Type: Journal Articles Status: Published Year Published: 2018 Citation: Gorden PJ, Kleinhenz MD, Wulf LW, Rajewski SJ, Wang C, Gehring R, Coetzee JF. Comparative plasma and interstitial fluid pharmacokinetics of flunixin meglumine and ceftiofur hydrochloride following individual and co-administration in dairy cows. J Vet Pharmacol Ther. 41(1):76-82, 2018. [PMID: 28731206]
• Type: Journal Articles Status: Published Year Published: 2017 Citation: Sidhu PK, Gehring R, Mzyk DA, Marmulak T, Tell LA, Baynes RE, Vickroy TW, Riviere JE. "Avoiding violative flunixin meglumine residues in cattle and swine." J Am Vet Med Assoc. 250: 2: 182-189, 2017.
• Type: Journal Articles Status: Published Year Published: 2018 Citation: Li M, Gehring R, Riviere JE, Lin Z. (2018). Probabilistic physiologically based pharmacokinetic model for penicillin G in milk from dairy cows following intramammary or intramuscular administrations. Toxicological Sciences, 164(1): 85-100. [PMID: 29945226]

Progress 09/01/15 to 08/31/16

Outputs
Target Audience:FARAD's immediate clients are practicing veterinarians, regulators and extension officers, but it ultimately protects the food consuming public and contributes to human Public Health by equipping these professionals with the best science available. Changes/Problems: Nothing Reported What opportunities for training and professional development has the project provided?This project directly supports one PhD graduate student, and partially supported three post-doctoral fellows. How have the results been disseminated to communities of interest?See data above on call center and internet access which is the primary route for information dissemination for FARAD. What do you plan to do during the next reporting period to accomplish the goals? Nothing Reported

Impacts
What was accomplished under these goals? FARAD has continued to operate its telephone hot-line and e-mail access systems throughout all of 2016. The regional access centers answeredspecific inquiries (entailing multiple drugs/contaminants;). The majority of these calls now come in over the internet rather than telephone. This volume is a 13% -26% increase over previous years. In the past, the majority of calls have been for dairy and beef cattle, followed by poultry, goats, swine, and sheep. Depending on species, each request may impact either a single animal or large herds or flocks. Situations leading to concerns about violative residues, ranged from intentional extralabel drug use for therapeutic purposes to accidental exposure and unavoidable exposure due to environmental accidents. In addition to specific cases that were submitted to the hot-line, users sought general information on drug and residue avoidance. The reasons for calls are very diverse and range from "ordinary requests" for drug withdrawal recommendations (related to extra-label drug use or accidental drug overdoses) to "extraordinary requests", which in the past have included pesticide and contaminant exposures (e.g, oil products spilled from freight trains), as well as disasters such as hurricanes on the US East Coast and the Fukushima nuclear disaster in Japan. The number of animals involved with each call can be quite substantial. During the report period, there were 50,377 unique visits to the FARAD website (daily average of 138 visits), which represents a net increase of 23.5% over the previous year. While 80.3% of website visits originated from IP addresses located within the United States, visits were logged from 153 separate countries, a slight increase over the previous year. In addition to the United States, other countries included in the top ten total visitors (high to low) were Canada, India, United Kingdom, Australia, Philippines, Germany, Taiwan, China and Mexico. The total number of page visits on www.farad.org increased by 29% over the previous year to 284,714 total page visits.Once again, the most highly-visited page was VetGRAM, with nearly 113,386 aggregate visits which represented a 28% increase over the previous year. Although these data reveal continued high volume of traffic on VetGRAM (> 310 page visits per day), overall use of VetGRAM has grown even more substantially with ever-increasing numbers of installs of our free VetGRAM apps for smart phones, including one for Android phones (866 downloads - 111 new this year) and a newly-released iPhone app with 43 downloads. Other highly viewed pages on the FARAD website included the Withdrawal Interval (WDI) Recommendation Lookup (58,178 visits - up 23%), the Withdrawal Date Calculator (27,041 visits - down 10%), the Restricted and Prohibited Drugs page (10,871 visits - up 16%) and Extra-Label Drug Use information page (7,608 visits - up 80%). The primary focus of KSU's work was to answer FARAD calls every third week, and develop physiologically-based pharmacokinetic and population pharmacokinetic models for selected drugs to predict tissue and milk residues in target populations. KSU also provided pharmacokinetic analysis services for all FARAD collaborators. The publications listed above document this productivity. Another focus area was to formalize the theoretical underpinnings of our pharmacokinetic models and algorithms through rigorous review and publication in the scientific literature . Finally, a full-time database developer was hired to continue work on the global database of veterinary products approved for food-producing animals.

Publications