# Presentation: 150100

## Establishing MRLs or Tolerances for Veterinary Drug and Chemical Residues in Food Animals

**Ronald E. Baynes, DVM, PhD**
**Center for Chemical Toxicology Research and Pharmacokinetics (CCTRP) **
**Food Animal Residue Databank**
**Department of Population Health and Pathobiology**
**College of Veterinary Medicine,**
**North Carolina State University**

## Outline of Talk

**Are these residues a risk to public health?**
**AMDUCA &  Pharmacology Concepts**
**Why do we need to establish safe levels?**
**How do various agencies in ****US****, ****EU****, ****UN**** establish these levels?**
**Proposed transparent method: A PAR**
** ****Summary of observations **

## Can people really get sick from residues?

**Yes!**
**In one 6 month period in 1993 more then 1,200 hospitalizations and 3 deaths in France and Spain were reported to have resulted from eating beef livers contaminated with the illegal growth promotant clenbuterol.**
**6/38 animals tested + at OK state fair in 1995.**
**Vet: 8 months & $80,000 for smuggling it into US in 1999.  **

**Why should I care?**

## - Over-The-Counter (OTC) Drugs

**Majority of animal drugs sold in US**
**Can still cause residues if not used according to label. **

**What are these drugs? **

## Prohibited Drugs

**Some drugs may **_***not***_**  be used on a dairy, even with a vet’s extra-label prescription.**
** **
**Chloramphenicol**
**Clenbuterol**
**Colloidal silver**
**Diethylstilbestrol (DES)**
**Dimethyl sulfoxide (DMSO)**
**Dipyrone**
**Enrofloxacin (Baytril®) **
**Glycopeptides (vancomycin)**
**Nitrofurazone/Furazolidone**
**Nitroimidazoles (metronidazole)**** **

**The LAW!**** **

## Accidental Exposure to Pesticides via Treated Pastures and Crop Residues

**While rarely fatal, animals grazing treated fields or crop residues can have their tissues and milk contaminated with pesticides or herbicides. There are usually prescribed times following  application after which animals can safely graze treated pastures. **

## AMDUCA

**Animal Medical Drug Use**
**Clarification Act of 1994**** **

**AMDUCA**

**Extra-label use of drugs has been**

**legalized and FDA/CVM has published**

**regulations for extra-label drug use **

**FARAD**** is a MAJOR source of ELDU information **

## Extra Label Drug Use Guidelines 

**Extra Label Drug Use Guidelines**** **
**1.****	****A ****valid veterinarian-client-patient relationship****, ****	****	****	****and careful diagnosis.**
** **
**2.****	****No currently marketed drug**** for the disease, or ****	****	****	****recommended dose is ineffective.**
** **
**3.****	****Records and other measures to ****identify the ****	****	****	****treated animal****(s).**
** **
**4.****	****Significantly ****extended withdrawal period****, no ****	****	****	****illegal residues**
**	****	****	**
**	****	****...****.but this info is not on the bottle!!!**
**	****	****...****what about pesticides or contaminants?****	**
**...****.....so where do we go from here?**

## Drug Residue Pharmacokinetics 

**Tolerance**

**Time**

**Ln**

**PPM**

**Marker**** **

**Residue**

**Withdrawal Time**

**Last Dose**

**Residue Elimination**

**Phase**

**Slope = kel**

**Drug Residue Pharmacokinetics **

## .....what if a larger dose was given or change in Cl or Vd ?

**...****..what if a larger dose was given or change in Cl or Vd ?**

## How is Tolerance Derived  for Oxytetracycline (LA 200)?? 

**How is Tolerance Derived **** for Oxytetracycline (LA 200)??**** **

** ****Where would you place the tolerance line for the Milk Data below**

## Slide 12

## Strategy for Deriving an Equivalent Tolerance or MRL (e.g., a PAR)-obtain an ADI from Toxicology Data

## Using foreign safety standards (e.g., MRLs)?

**There are several limitations here:**
**Foreign MRLs  ********  U.S. Tolerances**
**therefore one cannot directly extrapolate from foreign MRL**
**Foreign methods differ from US methods**
**partitioning of ADI vary**
**gut flora effects are considered **
**NOELs are calculated differently from US**
**MRL determination is not always strickly health-based**
**i.e. residue depletion data is utilized early in the process**

## Relationship between U.S. Tolerances and JECFA MRLs

## Strategy for Deriving a PAR-Definitions

**A PAR is similar to US FDA definition of a SC**
**PAR  =  **_**ADI (mg drug/kg Body Wt./day) *  Body Wt**_**.****	****       Food Consumption Values (kg food/day)**
**ADI   =  ****NOEL (mg/kg Body Wt./day) /  Safety Factor**
**NOEL  =  ****Greatest amount of drug found to cause  ****	****	****   no detectable adverse effect in ****lab animals****.**

## Safety Factors

- 	**The NOEL is divided by safety factors that may **_**vary from 100 to 1000**_** depending on the toxicology study. The following safety factors have been adapted by the US FDA**
** ****Safety Factor for Chronic Studies****	****	****100**
** ****Safety Factor for Sub-Chronic Studies****	****	****1000**
** ****Safety Factor for Repro/Terat Studies****	****	****100**
**	****	****	****With clear maternal Tox****	****1000**

##  Food Consumption Values (FCVs)

_**Tissue**__**	**__**	**__**Kilograms Consumed**__**	**__**	**__**	**__**	**_
**Muscle****	****	****	****0.3**
**	****	****Liver****	****	****	****	****0.1**
**	****	****Kidney****	****	****	****0.05**
**	****	****Fat****	****	****	****	****0.05**
**	****	****Eggs****	****	****	****	****0.1**
**	**_**	**__**Milk**__**	**__**	**__**	**__**	**__**1.5**__**	**_
- _	__	__	__	_** **
**US FDA assumes: **
**(1) individuals eat more edible muscle than organ tissue, **
**(2) individuals do not eat a full portion of meat product from another spp **
**(3) milk and egg products are consumed in addition to edible tissue**

## Strategy for Deriving a PAR-using the ADI to get a PAR

**what do we do with this ADI in order to get at a ****Safe level**** ??**

## Slide 20

## Deriving a Provisional Tolerance or MRL

## Strategy for Deriving a PAR-summary of partitioning procedures

**PARs A ****tissue(s) or milk**** = **_**50% ADI (mg/kg body wt.) * 60 kg**_
**	****	****	****	****	****	****FCV for tissue(s) or milk **
** ****PARs B ****tissue(s) or milk**** = **_**{100% ADI * 60 kg} / tissues & milk**_
**	****	****	****	****	****	****FCV for tissue(s) or milk**
**PARs C ****tissue(s)**** ****	****    =  **_**{**__**50% ADI * 60 kg}  / # tissues**__**	**_**	****	****	****	****	****FCV for tissue(s) **
**	****	****(PARs C****milk**** is similar to PARs A above)**

## Simulation of PARs for TetracyclineJECFA ADI = 0 - 1.8 mg per 60 kg ; US ADI = 1.5 mg per 60 kg

**	****	****	****PAR****	****PAR****	****PAR****	****U.S.****	****U.S.****	**** ****EU****	****JECFA**
**	****	****	****  **_**A**__**	**_**   **_**B**__**	**_**   **_**C**__**	**__*****__**Tol.**__**	**__**Tol**__**.**__**	**__**MRL**__**	**__**  MRL**_
**Muscle****	**** **_**2.5**_**	**** 1.0****	**** 0.63****	**** ****0.25****	****   2****	**** ****0.1****	****  0.2**
**Liver****	****	**** **_**7.5**_**	**** 3.0****	**** 1.89****	**** ****0.25****	****   6****	**** ****0.3****	****  0.6**
**Kidney****	**** **_**15.0**_**	**** 6.0****	**** 3.75****	**** ****0.25****	****  12****	**** ****0.6****	**** 1.2**
**Fat****	****	**** **_**15.0**_**	**** 6.0****	**** 3.75****	**** ****0.25****	****  12****	**** ****NA****	**** NA**
**Milk****	****	**** **_**0.5**_**	**** 0.2****	**** 0.5****	**** ****0.08****	****  0.3****	**** ****0.1****	****  0.1**
**TMDI****	****(mg)****	**** **_**1.5**_**	**** 1.5****	**** 1.5****	**** 0.25****	****  **_**2.85**_**	**** ****0.24****	****  0.33**

## How is US Tolerance Derived  for Oxytetracycline (LA 200)?? 

**How is US Tolerance Derived **** for Oxytetracycline (LA 200)??**** **

** ****ANSWER: US Tolerance is 0.3 ppm similar to PARs A procedure.   ****BUT, EU MRL is 0.1 ppm.  ****If we in the US use foreign approval MRL or WDT, ****this means we throw away more milk**** **

**------------------------------------------------------ MRL**

**-------------------------------------------- ****US Tolerance**

## Summary of Results

**Little or no correlation between U.S. Tol and foreign MRLs**
**e.g., U.S. Tol. For tetracycline is 20X  >>>  EU MRL**
**this can result in a TMDI >>> ADI**
**___****_----------------------------------------------------**
**PARs and PATs are comparable to:**
**U.S. Tolerances****	****ivermectin, tetracycline**
**U.S. SC****	****	****	****ivermectin (pigs only)****	**
**Foreign MRLs****	****	****dexamethasone, azaperone**
**Partitioning methods by agencies are inconsistent:**
**florfenicol & doramectin: 100% ADI allocated to tissues; 0% to milk**
**tetracycline: 40% ADI allocated to tissues; 60% to milk.**

## Conclusions

**Enforceable residue levels can be established on ****health-based principles****.**
**PARs  or  PATs  ensures that the TMDI  << ADI.**
**These values may be used in the advent of ****accidental exposure to contaminants**** or extralabel **_**drug**_** use in food animals to estimate a safe withdrawal interval.**
**These ****methods are transparent****, and may encourage ****international harmonization**** and trade**.

## Slide 27