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.: 1000689
• Grant No.: 2013-41480-21001
• Cumulative Award Amt.: $292,307.00
• Proposal No.: 2013-04914
• Project Start Date: Sep 1, 2013
• Project End Date: Aug 31, 2015
• Grant Year: 2013
• Program Code: [FARAD]- Food An. Res. Avoidance Database,FARAD

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 31 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 so extensive computational modeling may be required to provide valid estimates for ensuring safe food. 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 which will improve its usefulness and utility as a decision support system. The five primary tasks include: 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 data from foreign drug compendia. Operation of the Regional Access Centers (RAC's) at NCSU, KSU, and UCD for provision of residue avoidance information, with access through the toll-free hotline and e-mail. Data entry, pharmacokinetic analysis, maintenance, and distribution of the FARAD files. 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. Develop and validate methods to allow extrapolative techniques to be used in providing information and advice in situations where no direct data currently 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 (telephone, internet) 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 also provides responses to drug and contaminant residue questions submitted to FARAD. 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. Collaboration between all institutions occurs on research projects that are necessary to validate the FARAD withdrawal interval estimates. 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 15 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 two summers ago using pass though funds from FDA to NIFA for this purpose.

Progress 09/01/13 to 08/31/15

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: There are no substantial changes planned for the next year of operations. We will try and secure funding for the global FARAD program. A continued problem is the lack of multiple year support which makes planning and hiring of new staff always problematic, especially with the increase in service calls experienced this year. What opportunities for training and professional development has the project provided? This project directly supports one PhD graduate student, and two post-doctoral fellows. How have the results been disseminated to communities of interest? FARAD has continued to operate its telephone hot-line and e-mail access systems throughout all of 2014-2015. The regional access centers answered over 2,704 specific inquiries (entailing multiple drugs/contaminants; average 52 calls per week). The majority of these calls now come in over the internet rather than telephone. This volume is a 26% increase over last year, which continues the trend of last year's 30% increase. The majority of calls remain 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; with a total estimated impact of 1.8 million animals. 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, as well as disasters such as Fukushima in Japan. The number of animals involved with each call can be quite substantial. During this last year, extraordinary inquiries related primarily to potential livestock exposure to oil products spoiled from freight trains. During the report period, there were 40,800 visitors to the FARAD website (daily average of 112 / day), which represents a net increase of 16.5% over the previous year. While 78% of website visitors originated from the United States, visits were logged from 150 as compared to 83 countries in the previous year. The top ten (high to low) were Canada, Philippines, India, United Kingdom, Brazil, Germany, Australia, Costa Rica, Mexico and Spain. The total number of page visits on www.farad.org increased more than two-fold to 220,300 page visits.Once again, the most highly-visited page was VetGRAM, with nearly 88,700 aggregate visits. Although this indicates high VetGRAM usage (> 240 page visits per day), the total represents a slight decline in aggregate page visits compared to the previous year (92,000), which is probably due to the increased number of installs of our free VetGRAM app for Android mobile phones, which have grown to 755. Other highly viewed pages on the FARAD website included the Withdrawal Interval Recommendation Lookup (47,224 visits), the Withdrawal Date Calculator (30,018 visits), the Restricted and Prohibited Drugs page (9,390 visits) and Extra-Label Drug Use information page (4,221 visits). A review of the most common operating systems among website visitors revealed a continuing growth in the number of visitors on devices with the Apple operating system (iOS) and provides a strong rationale to develop and launch an iPhone app this year. What do you plan to do during the next reporting period to accomplish the goals? The 2015-2016 FARAD project year will be focused on the essential tasks outlined above, including answering FARAD requests, providing pharmacokinetic services to all FARAD sites and analyzing data in collaborative projects (USDA-ARS/ FDA-CVM flunixin and penicillin studies), continuing developing pharmacokinetic meta-analysis tools that allow FARAD responders to fully utilize published studies to avoid meat and milk residues in minor use species and in the presence of disease. We continue to explore how modern mixed-effects pharmacokinetic modeling tools, widely used in human drug development, can be adapted to the animal health production environment specifically to predict violative residues that only occur in a very small numbers of animals. Our goal is to help determine how these outlier individuals can be identified. With the launching of the Iowa State collaboration, we hope to be able to validate FARAD withdrawal time estimates. Prof. Gehring of KSU is the Kansas FARAD Project Director to handle day to day activities and coordinate pharmacokinetic modeling exercises. Prof. Riviere participates in these activities as well as having primary responsibility of managing national FARAD directions and opportunities. A major focus this year will be to continue coordinating development of the global FARAD project called GVDRAKS (Global Veterinary Drug Residue Avoidance Knowledge System) to STDF/WTO. KSU is the primary coordinator of this project with our CABI partner. Our database manager and biomathematics post-doctoral fellow are involved in scoping and developing a pilot database to assess feasibility of the project. The actual FARAD tasks undertaken this year will be a result of discussions between the four collaborating FARAD sites and what type of emergencies arise over the next year.

Impacts
What was accomplished under these goals? The primary focus of KSU's work was to answer FARAD calls every third week, complete the meta-analysis of comparative pharmacokinetic data of 85 drugs in the FARAD database to assess the applicability of making interspecies extrapolations when data is scarce, develop a framework for multi-species mixed-effect pharmacokinetic model that could be used to predict tissue residues of drugs given to diseased animals, and provide pharmacokinetic analysis services for all FARAD collaborators. The publications listed below (5,6,7) document this productivity. Two post-doctoral fellows at KSU were engaged in this work. The large flunixin diseased dairy cow trial conducted at USDA/ARS in Fargo was also completed this year (8). This was an outgrowth of FSIS reported flunixin milk violations, FARAD clinical studies of flunixin disposition in mastitis in dairy cows (4 ) and FARAD modeling predictions that disease-induced changes in flunixin metabolism given to cows for label indications, result in violative residue even if administered according to label directions The final focus was to submit the proposal for the global FARAD in conjunction with CABI to the WTO/ STDF. KSU also has the national coordinating functions for the US FARAD program.

Publications

• Type: Journal Articles Status: Published Year Published: 2013 Citation: Wu H, Baynes RE, Leavens T, Tell LA, Riviere JE. Use of population pharmacokinetic modeling and Monte Carlo simulations to capture individual animal variability in the prediction of flunixin withdrawal times in cattle. J. Vet. Pharmacol. Therap. 36: 248-257, 2013. [PMID 22712521]
• Type: Journal Articles Status: Published Year Published: 2014 Citation: Huang Q, Riviere JE: The application of allometric scaling principles to predict pharmacokinetic parameters across species. Expert Opinion Drug Metab. Toxicol. 10: 1241-1253, 2014. [24984569]
• Type: Journal Articles Status: Published Year Published: 2015 Citation: Kissel LW, Leavens TL, Baynes RE, Riviere JE, Smith G. Comparison of flunixin pharmacokinetics and milk elimination in healthy cows and cows with mastitis. J.Am.Vet.Med.Assoc. 246: 118-125, 2015 [25517334]
• Type: Journal Articles Status: Published Year Published: 2015 Citation: Lin Z, Li M, Gehring R, Riviere JE. Development and application of a multi-route physiological based pharmacokinetic model for oxytetracycline in dogs and humans. J.Pharm.Sci. 104: 233-243, 2015. [25407474]
• Type: Journal Articles Status: Published Year Published: 2015 Citation: Li M, Gehring R, Riviere JE. A framework for meta-analysis of veterinary drug pharmacokinetic data using mixed-effect modeling. J. Pharm. Sci. 104: 1230-1239, 2015. [25641543]
• Type: Journal Articles Status: Published Year Published: 2015 Citation: Huang Q, Gehring R, Tell LA, Li M, Lin Z, Riviere JE. Interspecies allometric meta-analysis of the comparative pharmacokinetics of 85 drugs across veterinary and laboratory animal species. J. Vet. Pharmacol. Therap. 38: 214-226, 2015 [25333341]
• Type: Journal Articles Status: Published Year Published: 2015 Citation: Smith DJ, Shelver WL, Baynes RE, Tell LA, Gehring R, Li M, Dutko T, Schroeder JW, Herges G, Riviere JE. Tissue residues after label and extra-label administration of flunixin meglumine to saline or lipopolysaccharide-exposed dairy cows. J. Agr. Food Chem. 2015 (Pre-pub on line) [25950946]
• Type: Journal Articles Status: Published Year Published: 2014 Citation: Shelver WL, Tell LA, Wagner S, Wetzlich S, Baynes RE, Riviere JE, Smith DJ., 2014. Comparison of ELISA and LC-MS/MS for the measurement of flunixin free acid plasma concentrations in beef cattle after intravenous and subcutaneous administration. J. Ag. Food Chem. doi:10.1021/jf304773p [PMID 23470029]
• Type: Journal Articles Status: Published Year Published: 2014 Citation: Baynes RE, Riviere JE (eds): Strategies for Reducing Drug and Chemical Residues in Food Animals: International Approaches to Residue Avoidance, Management and Testing. New York: Wiley, 2014.
• Type: Journal Articles Status: Published Year Published: 2014 Citation: Li M, Gehring R, Tell L, Baynes R, Huang Q, Riviere JE: Interspecies mixed effect pharmacokinetic modeling of penicillin G in cattle and swine. Antimicrob. Agents Chemother. 58: 4495-4503, 2014. [24867969]

Progress 09/01/13 to 08/31/14

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: There are no substantial changes planned for the next year of operations. We will try and secure funding for the global FARAD program. A continued problem is the lack of multiple year support which makes planning and hiring of new staff always problematic, especially with the increase in service calls experienced this year. What opportunities for training and professional development has the project provided? This project directly supports one PhD graduate student, and two post-doctoral fellows. How have the results been disseminated to communities of interest? FARAD has continued to operate its telephone hot-line and e-mail access systems throughout all of 2013-2014. The regional access centers answered over 2,145 specific inquiries (entailing multiple drugs/contaminants; average 34 calls per week). Ninety percent of these calls now come in over the internet rather than telephone. This volume is a 30% increase over last year. The majority of calls remain for dairy and beef cattle, followed by poultry, goats, swine, and sheep, a pattern which has not changed. Depending on species, each request may impact either a single animal or large herds or flocks; with a total estimated impact of over 3 million animals. 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. During the past year, there were more than 35,000 visitors to the FARAD website for an average of 95 visitors per day. While the majority of these visits originated from the US (~76%), visits were logged from 83 countries with the 10 highest number of visits coming from (high to low) Philippines, Canada, India, Germany, United Kingdom, Australia, Mexico, China, Pakistan and Taiwan. The FARAD web page viewed most frequently was the Veterinarian's Guide to Residue Avoidance Management or VetGRAM, with 92,001 aggregate views through the website and the mobile device-friendly website. Other highly viewed web pages included a page for searching FARAD's published recommendations for drug withdrawal intervals following extralabel use (WDI Lookup -43,734 views), an on-line tool for calculation of withholding periods based on specified treatment dates (WD Calculator - 21, 348 views) and several web pages associated with regulatory rules, definitions, prohibited drugs in food animals and other related information (20,024 total views). What do you plan to do during the next reporting period to accomplish the goals? The 2014-2015 FARAD project year will be focused on the essential tasks outlined above, including answering FARAD requests, providing pharmacokinetic services to all FARAD sites and analyzing data in collaborative projects (USDA-ARS/ FDA-CVM flunixin and penicillin studies), continuing developing pharmacokinetic meta-analysis tools that allow FARAD responders to fully utilize published studies to avoid meat and milk residues in minor use species and in the presence of disease. We continue to explore how modern population pharmacokinetic modeling tools, widely used in human drug development, can be adapted to the animal health production environment specifically to predict violative residues that only occur in a very small numbers of animals. Our goal is to help determine how these outlier individuals can be identified. Prof. Gehring of KSU is the Kansas FARAD Project Director to handle day to day activities and coordinate pharmacokinetic modeling exercises. Prof. Apley is an active participant in mitigating beef residues while Prof. Kukanich provides analytical expertise. Prof. Riviere participates in these activities as well as having primary responsibility of managing national FARAD directions and opportunities. A major focus this year will be to coordinate development of the global FARAD proposal to STDF/WTO. KSU is the primary coordinator of this project with our CABI partner. Our database manager is involved in scoping and developing a pilot gFARAD to assess feasibility of the project. The actual tasks undertaken will be a result of discussions between the four collaborating FARAD sites and what types of emergencies arise over the next year.

Impacts
What was accomplished under these goals? This was the second year and first full year of Kansas State University’s participation in the FARAD program. [Please see progress reports for CA, FL and NC for program achievements completed by those regions.] The primary focus of KSU’s work was to answer FARAD calls every third week, conduct a meta-analysis of comparative pharmacokinetic data across 88 drugs in the FARAD database to assess the applicability of making interspecies extrapolations when data is scarce, develop a multi-species mixed-effect pharmacokinetic model that could be used to predict tissue residues of drugs given to diseased animals, and provide pharmacokinetic analysis services for all FARAD collaborators. The final focus was to develop the proposal for the global FARAD in conjunction with CABI that led to the successful awarding of a STDF planning grant. FARAD also has the national coordinating functions for the US FARAD program.

Publications

• Type: Journal Articles Status: Accepted Year Published: 2013 Citation: Wu H, Leavens T, Baynes RE, Tell LA, Riviere JE: Use of population pharmacokinetic modeling and Monte Carlo simulations to capture individual animal variability in the prediction of flunixin withdrawal times in cattle. J. Vet. Pharmacol. Therap. 36: 248-257, 2013. Kissel LW, Baynes RE, Riviere JE, Smith GW: The occurrence of flunixin residues in bovine milk samples from the United States. J. Food Additive Contaminants Part A. 30: 1513-1516, 2013. Shelver WL, Tell LA, Wagner S, Wetzlich S, Baynes RE, Riviere JE, Smith DJ: Comparison of ELISA and LC-MS/MS for the measurement of flunixin free acid plasma concentrations in beef cattle after intravenous and subcutaneous administration. J. Ag. Food Chem. 61: 2679-2686, 2013. DeDonder K, Gehring R, Baynes RA, Tell LA, Vickroy TW, Apley MD, Riviere JE: FARAD Digest: Procaine penicillin G withdrawal intervals in cattle: An update based on new sampling protocols. J. Am. Vet. Med. Assoc. 243: 1408-1412, 2013. Wu H, Baynes RE, Tell LA, Riviere JE: Prediction of flunixin tissue residue concentrations in livers from diseased cattle. Food Chemical Tox. 62:876-879, 2013.
• Type: Journal Articles Status: Awaiting Publication Year Published: 2014 Citation: Baynes RE, Riviere JE (eds): Strategies for Reducing Drug and Chemical Residues in Food Animals: New York: John Wiley (In Press, 2014). Kissel LW, Leavens TL, Baynes RE, Riviere JE, Smith G. Comparison of flunixin pharmacokinetics and milk elimination in healthy cows and cows with mastitis. J.Am.Vet.Med.Assoc. 2014 (In Press) Li M, Gehring R, Tell L, Baynes R, Huang Q, Riviere JE: Interspecies mixed effect pharmacokinetic modeling of penicillin G in cattle and swine. Antimicrobial Agents Chemotherapy (In Press) Huang Q, Riviere JE: Allometric scaling to predict pharmacokinetic parameters across species. Expert Opinion Drug Metab. Toxicol. (In Press)