Source: KANSAS STATE UNIV submitted to
FOOD ANIMAL RESIDUE AVOIDANCE DATABANK (FARAD)
Sponsoring Institution
National Institute of Food and Agriculture
Project Status
TERMINATED
Funding Source
OTHER GRANTS
Reporting Frequency
Annual
Accession No.
1010250
Grant No.
2016-41480-25729
Project No.
KS8012017
Proposal No.
2016-07555
Multistate No.
(N/A)
Program Code
FARAD
Project Start Date
Sep 1, 2016
Project End Date
Aug 31, 2019
Grant Year
2016
Project Director
Lin, Z.
Recipient Organization
KANSAS STATE UNIV
(N/A)
MANHATTAN,KS 66506
Performing Department
Anatomy & 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 34 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 up to date 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 ensure 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
100%
Research Effort Categories
Basic
25%
Applied
75%
Developmental
0%
Classification

Knowledge Area (KA)Subject of Investigation (SOI)Field of Science (FOS)Percent
7115010106040%
3145010115030%
7115010208030%
Knowledge Area
711 - Ensure Food Products Free of Harmful Chemicals, Including Residues from Agricultural and Other Sources; 314 - Toxic Chemicals, Poisonous Plants, Naturally Occurring Toxins, and Other Hazards Affecting Animals;

Subject Of Investigation
5010 - Food;

Field Of Science
1060 - Biology (whole systems); 2080 - Mathematics and computer sciences; 1150 - Toxicology;
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'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 from our research.FARAD personnel at UCD search the scientific literature for information about chemical elimination from food producing animals, extract relevant information, and enter it into a computer databank for easy retrieval. Because there are many factors which affect how rapidly an animal eliminates a residue; information about diet, age, sex, breed, and disease are taken into consideration. The databank allows existing curated information to be efficiently brought to bear "real time" on residue problems arising from exposure to environmental contaminants or from extralabel drug therapy. FARAD at UF collects and makes available a compilation of FDA approved drugs from which approved withdrawal times can be obtained. 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 as well as mobile platforms for smartphone access. These FARAD products provide information for users about drugs that are approved for treating animal diseases, and the associated withholding times for milk, eggs, honey and preslaughter withdrawal times for meat. A calendar function is integrated into these programs to aid the veterinarian in the field. When information is not sufficient, direct access to FARAD experts is available through the Regional Access Centers at KSU, NCSU and UCD. FARAD provides multilayered service to persons most critical to 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 doctoral-level professional staff to provide information on prevention and mitigation of violative 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 a unique provider of such services. Expert system software that used to supplement printed compendia to helped drug users make more informed decisions, had been developed and are now available in a single portal, VetGRAM, available at FARAD's website maintained at UF. 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 specific extra-label drug use or contaminant scenario at hand. Since residue data continues to be published daily in scientific journals and regulatory reports, maintenance and addition of new data by UCD are essential to providing accurate advice and mitigation of potential residue exposures. This is especially important since residue depletion data in food animals is sparse and FARAD predictions would be significantly strengthened with additional field data under usage conditions (e.g. in diseased animals for which the drug is labeled).FARAD has maintained a toll-free number since 1996: 1-888-US-FARAD to respond to specific inquiries for assistance. The FARAD website (www.farad.org) provides users with additional residue avoidance resources which reduce the need for more specialized and intensive telephone consultations. These resources include the FARAD Digest series, links to species-specific pages where information is collated in a user-friendly manner for producers and veterinarians focused on a specific food production system, and relevant news items. FARAD also provides free access to its extensive bibliographic database through the website. Over the past 19 years, with encouragement from the American Veterinary Medical Association (AVMA), the FARAD Digest series have been published in the Journal of the AVMA. These digests provide well-documented information about extralabel drug withdrawal intervals.FARAD is officially allied with the Centre for Applied Biosciences International's (CABI) since 2003 where FARAD files are included in the various issues of their Animal Health and Production Compendium. ?

Progress 09/01/16 to 08/31/19

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 at Kansas State University (KSU) related to this grant. Initially, the PI of this grant was Dr. Ronette Gehring, and the Co-PIs were Dr. Jim Riviere, Dr. Zhoumeng Lin, and Dr. Majid Jaberi-Douraki. However, in May 2017, Dr. Jim Riviere retired from Kansas State University. In September 2017, Dr. Ronette Gehring accepted an offer of full professor and chair at the University of Utrecht and left KSU. 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. Dr. Zhoumeng Lin took over as the PI of this award at KSU in November 2017. 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 in this final report 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 two undergraduate students, one PhD student, and two postdoctoral 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). Additionally, we presented our research findings in the Annual Meetings of Society of Toxicology in 2017, 2018, and 2019. 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 demonstrated remarkable growth throughout the past five years in terms of both the number of residue-related questions received via our telephone hotline plus our internet-based portal as well as the number of visits to our web-based information resources at www.farad.org. FARAD has continued to operate its telephone hot-line and e-mail access systems throughout the past year, which produced continued growth in the number of calls compared to the previous year. During 2018, the regional access centers answered 3,645 specific inquiries (entailing multiple drugs/contaminants) that directly involved approximately 6.9 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 unquantifiable. The majority of these inquiries were submitted via the World Wide Web and remain focused on small production poultry (33%) followed by dairy and beef cattle (23%), then small ruminants (27%), swine (11%), rabbits (1%) and other (3%). 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 the 2018-2019 project report period, there were 54,798 visitors to the FARAD website (daily average of 150), which represents a net increase of 25.9% over the previous year. While the preponderance of these visits (40,339 or 78%) still originated from IP addresses located within the United States, it was interesting to note that the proportion of US-based visits showed a decline from 83% in 2017, which is the first time such a decline has been noted. In total, website visits originated from a total of 166 countries, with the top ten numbers of non-US visitors being from (high to low) Canada, India, United Kingdom, France, Australia, Brazil, China, Philippines and Mexico. The total number of visitors to www.farad.org increased by more than 35% from the previous year with 89,488 total page visits. One continued trend in 2018 was the sustained rebound in the number of total visits to VetGRAM, which increased to 127,052 page views following a sharp decline in 2016. Although we had suspected that the sharp decline in VetGRAM use during 2016 might possibly be associated with increased use of free mobile phone apps, data from the past two years reveal a return to a continued high demand for the internet-based VetGRAM platform (348 page visits per day). Other highly viewed pages on the FARAD website included the Withdrawal Interval (WDI) Recommendation Lookup, the Veterinary Feed Directive, the Withdrawal Date Calculator, the Restricted and Prohibited Drugs page and Extra-Label Drug Use information pages. During the past year, several species specific web pages were created to provide resources that were targeted toward users with specific interests in honey bees, dairy cattle, poultry or small ruminants. 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 (515 active installs) and the iOS-based app for iPhones (408 active installs). The majority of mobile app installations have been with US-based phones including 510 (99%) of Android phone installs and 372 (91%) of iPhone installs. With the continued increased use of mobile phone apps, particularly among US-based users, it is possible that mobile app use has contributed to the slight decline in the proportion of US-based visitors to FARAD websites by traditional desktop computer users. The primary focus of KSU's FARAD work was to develop physiologically based pharmacokinetic models for selected drugs to predict tissue and milk residues and withdrawal intervals in food-producing animals. KSU also provided pharmacokinetic analysis services for all FARAD collaborators. In the last project year alone, KSU FARAD team published a PBPK model for penicilllin G in sows and a PBPK model for flunixin meglumine in swine and cattle. Some of these PBPK models were also converted to web-based interfaces for use by FARAD responders. KSU FARAD team also collaborated with scientists in other FARAD sites and published several collaborative papers. The publications listed in this final report represent the accomplishments that KSU FARAD team has achieved in the past three years under the support of this grant. These publications also support the productivity of the KSU FARAD team.

Publications

  • 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. [PMID: 26751035]
  • 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. [PMID: 27108460]
  • 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. [PMID: 27863483]
  • 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. [PMID: 27302389]
  • 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. [PMID: 27227502]
  • 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. [PMID: 28467745]
  • 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. [PMID: 28509644]
  • 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. [PMID: 28058945]
  • 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: Li M, Gehring R, Riviere JE, Lin Z. Probabilistic Physiologically Based Pharmacokinetic Model for Penicillin G in Milk From Dairy Cows Following Intramammary or Intramuscular Administrations. Toxicol Sci. 164:85-100, 2018. [PMID: 29945266]
  • Type: Journal Articles Status: Published Year Published: 2018 Citation: Stafford EG, Tell LA, Lin Z, Davis JL, Vickroy TW, Riviere JE, Baynes RE. Consequences of fipronil exposure in egglaying hens. J Am Vet Med Assoc. 253:57-60, 2018. [PMID: 29911954]
  • Type: Journal Articles Status: Published Year Published: 2018 Citation: Martin KL, Clapham MO, Davis JL, Baynes RE, Lin Z, Vickroy TW, Riviere JE, Tell LA*. Extra-label drug use in small ruminants. Journal of the American Veterinary Medical Association, 253(8):1001-1009. [PMID: 30272520]
  • Type: Journal Articles Status: Published Year Published: 2019 Citation: Yang F, Lin Z, Riviere JE, Baynes RE. (2019). Development and application of a population physiologically based pharmacokinetic model for florfenicol and its metabolite florfenicol amine in cattle. Food and Chemical Toxicology, 126:285-294. [PMID: 30825586]
  • Type: Journal Articles Status: Published Year Published: 2019 Citation: Li M, Mainquist-Whigham C, Karriker LA, Wulf LW, Zeng D, Gehring R, Riviere JE, Coetzee JF, Lin Z. (2019). An integrated experimental and physiologically based pharmacokinetic modeling study of penicillin G in heavy sows. Journal of Veterinary Pharmacology and Therapeutics, 42(4):461-475. [PMID: 31012501]
  • Type: Journal Articles Status: Published Year Published: 2019 Citation: Li M, Cheng YH, Chittenden JT, Baynes RE, Tell LA, Davis JL, Vickroy TW, Riviere JE, Lin Z. (2019). Integration of Food Animal Residue Avoidance Databank (FARAD) empirical methods for drug withdrawal interval determination with a mechanistic population-based interactive physiologically-based pharmacokinetic (iPBPK) modeling platform: example for flunixin meglumine administration. Archives of Toxicology, 93(7):1865-1880. [PMID: 31025081]
  • Type: Journal Articles Status: Published Year Published: 2019 Citation: Clapham MO, Martin KL, Davis JL, Baynes RE, Lin Z, Vickroy TW, Riviere JE, Tell LA. (2019). FARAD Digest: Extra-label Drug Use in Wildlife and Game Animals. Journal of the American Veterinary Medical Association, 255(5):555-568.


Progress 09/01/17 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). 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. Dr Zhoumeng Lin took over as contact PI of this award at KSU. The specific aims and goals of the proposal had been 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. What opportunities for training and professional development has the project provided?This project directly supported one PhD graduate student and a post-doctoral fellow. 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). Additionally, we presented our research findings in the Annual Meeting of Society of Toxicology in San Antonio in March, 2018. What do you plan to do during the next reporting period to accomplish the goals?We plan to continue to improve the web-based PBPK framework. In addition, we plan to continue writing the manuscript describing the flunixin PBPK model in swine and cattle and then publish this manuscript.

Impacts
What was accomplished under these goals? Overall FARAD Program Usage. 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 the report period, 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. KSU Project Progress in the 2017-2018 project year: In the previous year, the KSU FARAD team has completed the following projects, including (1) a population physiologically based pharmacokinetic (PBPK) model for penicillin G in market age swine and beef cattle, (2) a population PBPK model for penicillin G in dairy cows, (3) a web-based graphical user interface (GUI) based on the population PBPK model for penicillin G in market-age swine and beef cattle which will be used as the basis for providing real time PBPK model simulations to FARAD responders, and (4) a population PBPK model for flunixin in market-age swine and beef cattle. Manuscripts describing Projects 1 and 2 have been published (Li et al., 2017, PMID: 28627373; Li et al., 2018, PMID: 29945226); the manuscript describing Project 4 is in preparation. The interface from Project 3 is now available online (https://pengpbpk.shinyapps.io/pen_g/ or https://pengpbpk.shinyapps.io/PBPK_mrgsolve/).

Publications

  • 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. [PMID: 26751035]
  • 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. [PMID: 27108460]
  • 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. [PMID: 27863483]
  • 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. [PMID: 27302389]
  • 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. [PMID: 27227502]
  • 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. [PMID: 28467745]
  • 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. [PMID: 28509644]
  • 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. [PMID: 28058945]
  • 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: Li M, Gehring R, Riviere JE, Lin Z. Probabilistic Physiologically Based Pharmacokinetic Model for Penicillin G in Milk From Dairy Cows Following Intramammary or Intramuscular Administrations. Toxicol Sci. 164:85-100, 2018. [PMID: 29945266]
  • Type: Journal Articles Status: Published Year Published: 2018 Citation: Stafford EG, Tell LA, Lin Z, Davis JL, Vickroy TW, Riviere JE, Baynes RE. Consequences of fipronil exposure in egg-laying hens. J Am Vet Med Assoc. 253:57-60, 2018. [PMID: 29911954]


Progress 09/01/16 to 08/31/17

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). 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 recently accepted an offer of full professor and chair at the University of Utrecht and will be leaving KSU at the end of September. 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. Dr Zhoumeng Lin will take over as contact PI of this award at KSU. The specific aims and goals of the proposal for 2017-1018 have been 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. What opportunities for training and professional development has the project provided?This project directly supports on PhD graduate students and a post-doctoral fellow. It also partially supports another PhD graduate student. 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?We plan to continue to develop PBPK models for drugs in food-producing animals, and then apply these models to predict drug extralabel withdrawal intervals. These models will help FARAD responders to answer withdrawal interval inquiries.

Impacts
What was accomplished under these goals? FARAD has continued to operate its telephone hot-line and e-mail access systems throughout all of 2016-2017. The regional access centers answered over 3,366 specific inquiries (entailing multiple drugs/contaminants). The majority of these calls now come in over the internet rather than telephone. This volume is a 10% increase over last year and remain focused on dairy and beef cattle (30%), followed by poultry (31%), then small ruminants (21%) and swine (13%). 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 include pesticide and contaminant exposures. The number of animals involved with each call can be quite substantial. During the report period, there were 60,904 unique visits to the FARAD website (daily average of 173 visits), which represents a net increase of 20.9% over the previous year. While 81.8% of website visits originated from IP addresses located within the United States, visits were logged from 169 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 remained relatively unchanged previous year at 289,282 (1.6% up) total page visits. One noteworthy change during 2016 was the significant drop in total visits to VetGRAM, which fell to 78,937 page views or a drop of 30% compared to the previous year. Although these data reveal a continued high volume of traffic on VetGRAM (> 210 page visits per day), the decline in VetGRAM usage during the past year may be associated with the substantial growth in the use of VetGRAM apps for smart phones. During the past year, new installs of our free VetGRAM apps continued to increase for both Android phones (520 downloads) as well as an iOS-based app for iPhones (280 downloads). Other highly viewed pages on the FARAD website included the Withdrawal Interval (WDI) Recommendation Lookup, 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: 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: 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: 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: 2016 Citation: DeDonder Keith D, Gehring Ronette, Riviere Jim E, Baynes Ronald E, Tell Lisa A, Vickroy Thomas W. 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: 2016 Citation: Baynes Ronald E, Dedonder Keith, Kissell Lindsey, Mzyk Danielle, Marmulak Tara, Smith Geof, Tell Lisa, Gehring Ronette, Davis Jennifer, Riviere Jim E. 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]