Human Food Safety Implications of Variation in Food Animal Drug Metabolism.

Zhoumeng Lin,Jim E Riviere,Christopher I Vahl

doi:10.1038/srep27907

Zhoumeng Lin, Jim E Riviere + Show 1 more

Open Access

https://doi.org/10.1038/srep27907

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Journal: Scientific Reports	Publication Date: Jun 1, 2016
Citations: 28	License type: CC BY 4.0

Affiliation: Kansas State University

Abstract

Violative drug residues in animal-derived foods are a global food safety concern. The use of a fixed main metabolite to parent drug (M/D) ratio determined in healthy animals to establish drug tolerances and withdrawal times in diseased animals results in frequent residue violations in food-producing animals. We created a general physiologically based pharmacokinetic model for representative drugs (ceftiofur, enrofloxacin, flunixin, and sulfamethazine) in cattle and swine based on extensive published literature. Simulation results showed that the M/D ratio was not a fixed value, but a time-dependent range. Disease changed M/D ratios substantially and extended withdrawal times; these effects exhibited drug- and species-specificity. These results challenge the interpretation of violative residues based on the use of the M/D ratio to establish tolerances for metabolized drugs.

Highlights

The cornerstone of regulatory chemical food safety programs is the monitoring of food products for violative chemical residues
To predict the metabolite to parent drug (M/D) ratio and evaluate how possible change of this ratio by disease is related to drug withdrawal times, we established a general physiologically based pharmacokinetic (PBPK) computational model for several commonly reported residue-violative drugs in cattle and swine (Fig. 1)
This finding is important because it challenges the fundamental assumption of using a fixed point estimate for the M/D ratio used in the current US FDA guideline for evaluating the safety of compounds in food-producing animals[1]

Summary

Introduction

The cornerstone of regulatory chemical food safety programs is the monitoring of food products for violative chemical residues. For edible products from food-producing animals, such as meat, milk or eggs, residue concentrations are determined based on jurisdictional-specific regulations that result in the determination of a tolerance (TOL) or maximum residue level (MRL) for specific drugs in a specific tissue for specific animal species[1] These are based on toxicological assessments related to consumption of meat containing the specific drug in the diet coupled to a safety factor that accounts for uncertainty which yields the acceptable daily intake (ADI). Subsequent studies are conducted employing this fixed ratio in larger number of healthy animals to determine a withdrawal time after cessation of drug administration that will deplete target tissues to below the TOL or MRL for the marker residue Due to these flaws, violative drug residues in the edible tissues of food-producing animals may occur when drugs are used in an extralabel manner or when disease is present even though the animals are slaughtered according to regulatory labeled withdrawal times[2,3]. We hypothesized that changes in the rate and extent of drug metabolism due to disease or species (or even breed) differences could alter this ratio, tissue residue levels and withdrawal times, making the marker residue a poor indicator of tissue exposure to unsafe drug concentrations

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