August 28, 2017
Authored and Edited by Pejmon Pashai; Mark J. Feldstein, Ph.D.
Studies have shown that residues of some veterinary drugs found in food products can cause adverse effects in humans. In some cases, adverse effects were observed after a single meal containing the drug residues. Traditional methods used to evaluate the potential toxicity of these residues, however, may not adequately address potential acute effects.
In the FDA’s Studies to Evaluate the Safety of Residues of Veterinary Drugs in Human Food, FDA recommends an acute reference dose (ARfD) approach to quantify safe levels for short-term exposure to veterinary drug residues. The Guidance discusses the nature and types of data that are useful in determining an ARfD, studies that may generate such data, and how to calculate an ARfD based on these data. But the Guidance does not mandate, among other things, when an ARfd analysis is required or establish specific exposure levels.
The Guidance takes a stepwise approach to evaluate the types of data to calculate an ARfD. First, it advises developers to consider all available data and information describing the physical, chemical, pharmacological, and toxicological characteristics of the drug. According to the Guidance, developers should focus on observations and data collected near the onset of repeated dose studies, as they more accurately represent short-term exposures.
If currently available sources of toxicity data are insufficient, developers are advised to consider acute endpoints in planned toxicity studies. Such endpoints include, but are not limited to, haematoxicity, immunotoxicity, hepatoxicity, developmental effects, reproductive effects, pharmacological effects, and other relevant clinical findings. In order to reduce the number of animals used for testing, the Guidance recommends modifying existing toxicology protocols to obtain relevant data. The Guidance provides a detailed example of a modified protocol, testing for acute specific endpoints in blood samples drawn from satellite test groups.
In the event additional information is needed to assess an ARfD, developers are advised to conduct specifically designed toxicity studies. Such studies should consider all available physical, chemical, pharmacological, toxicological information, and other functional parameters of the drug, such as Mode of Action.
To calculate an ARfD, developers should identify an appropriate point of departure (POD), which is the point on a dose-response curve at which toxicological effects become apparent. Additionally, developers should quantify uncertainty factors, which account for animal variability, interspecies extrapolation, quality of data, severity of response, etc. The specific ARfD is calculated by dividing the POD by an enumeration of the uncertainty factors. The calculated ARfD can be expressed as an amount of the substance on a per person or body weight basis.
While the Guidance represents FDA’s current perspective on the toxicity of short-term exposure to veterinary drug residues, it does not establish legally enforceable obligations. From a policy standpoint, the Guidance is part of a broader initiative by FDA to harmonize international regulations in order to reduce the differences in technical requirements for drug development among domestic and foreign regulatory agencies. The recommendations in the Guidance aim to bring greater clarity to foreign and domestic developers in determining the toxicity of veterinary drugs residues.
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