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U.S. Department of Health and Human Services

Animal & Veterinary

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by Dan J. Donoghue, Ph.D.
FDA Veterinarian Newsletter January/February 1998 Volume XIII, No I

The Center for Veterinary Medicine (CVM) commits significant resources towards protecting the human food supply by evaluating and eliminating potentially toxic levels of veterinary drug residues and contaminants which may be deposited in edible animal tissues. As part of this goal, CVM's Office of Research has ongoing laboratory research programs which investigate the transfer and uptake of drug residues and other contaminants in food products. As a member of this team, our laboratory evaluates the kinetics of contaminant transfer into eggs and has recently proposed a model to predict the pattern of residue transfer into egg yolks. The importance of this type of work has recently been highlighted by the recent reports of contamination of poultry feed with chlordane in the midwest and dioxin in the south and the potential for transfer into edible poultry products.

Eggs are an extremely important human food commodity. Each year, approximately 220 eggs are consumed, on average, by each individual in this country. Many of these eggs are eaten as further processed foods such as ice cream, bakery products, etc. Residues in eggs may be produced by exposing laying hens to drugs or contaminants in a number of ways. These include: 1) illegal or extra-label uses of drugs, 2) use of feed unintentionally cross-contaminated during feed mixing, 3) use of mislabeled feed and 4) pesticide, chemical or heavy metal contamination of feed ingredients or water.

Our laboratory's strategy to investigate contaminant transfer into eggs has taken a three-pronged approach. These approaches are: 1) use of traditional feeding studies to investigate transfer of an individual drug into eggs, 2) development of models to predict the pattern of contaminant transfer for a number of different chemical compounds, and 3) collaborative efforts to develop methods to identify if contaminant transfer is taking place.

Many veterinary drugs are fed to poultry to enhance growth rates, feed efficiency, egg production or for therapeutic reasons. Our laboratory has evaluated transfer rates of some of these drugs using traditional feeding studies. By adding the compound of interest to the feed and following depletion patterns, we have quantitated residue levels in eggs for the organic arsenicals, roxarsone and arsanilic acid and oxytetracycline. Feeding laying hens various doses of arsenicals, we discovered that arsenic levels in the whole egg did exceed the 500 ppm tolerance established for whole eggs by the FDA (Donoghue et al., 1994). In addition, we determined that 95 % of the arsenic was preferentially deposited in the egg yolk. In the case of the antibiotic, oxytetracycline (OTC), the opposite pattern of transfer seems to occur. Instead of preferential deposition in the yolk, our results indicate that OTC seems to preferentially deposit in albumen (Donoghue et al., 1997, submitted). Preferential deposition into egg components has regulatory significance since a significant proportion of eggs produced are separated into either yolk or albumen and sold separately for further processing. Just consider, of the average consumption of 220 eggs a year how often are you eating whole eggs such as scrambled or poached eggs? Many consumers get their egg products in further processed foods and therefore, it would be prudent to establish tolerances on an egg component basis (albumen or yolk) and not a whole egg basis.

Although these types of traditional feeding studies have provided useful information, they are only valuable for regulatory decisions for the particular drugs and doses used in that one study. Since these studies can take years to perform, it is not conceivable to investigate all drugs and titrations necessary for future regulatory decisionmaking. In an effort to provide the FDA with timely assessment of the potential for residue contamination for a variety of chemical compounds, our laboratory is developing prediction models for residue transfer into eggs. The intent is to identify underlying physiological mechanisms responsible for regulating residue transfer and mathematically describing these relationships. Factors such as the: 1) dynamic nature of yolk or albumen formation, 2) propensity of the drug to transfer into either albumen or yolk (drugs physicochemical properties), and/or 3) a drug's plasma half-life may all contribute or interact to affect the quantity of drug transfer or the duration of time eggs are laid containing residues.

Recently, our laboratory identified the important role the ovary performs in regulating drug transfer into developing egg yolks (Donoghue et al., 1996). Yolks develop in the ovary over a period of months and, even when contaminant transfer was limited to just a 24-hour period, yolks that are weeks to months from ovulation incorporated and stored residues. Interestingly, the patterns of residue transfer into yolks were similar for different types of contaminants. In separate, replicated studies, we determined that two dissimilar classes of antibiotics (ampicillin or oxytetracycline) or the pesticide, lindane, all had similar patterns of residue uptake into developing egg yolks. This potentially universal physiological regulation of residue transfer into egg yolks has been used to develop the following mathematical prediction model for residue transfer for all types of chemical compounds. Our model is as follows:




It is beyond the scope of this article to define and give examples of our model, but for interested readers, this information can be obtained from our paper in Journal of Food Protection (Donoghue, et. al., 1997; in press) or by contacting the author.

The predictive pattern of residue uptake into developing yolks is only one consideration in evaluating transfer into whole eggs. Models factoring the availability of contaminants at the level of the ovary (plasma residue levels), degradation of residues stored in the developing egg yolks (residues' stability), influence of variable feed intakes, etc. also need to be considered. In addition, model predictions need to be developed for residue transfer into egg albumen. Studies are currently underway or completed which address these issues. For example, we recently published our results examining ampicillin transfer and depletion levels in laid eggs (Donoghue, et al., 1997).

Results of these studies have significant human food safety implications. Due to the unusual nature of egg formation, many principles of residue transfer for domestic livestock do not apply to birds. Even if hens are dosed for only one day, it is possible, laid eggs will contain varying (even increasing) levels of residues, days to a number of weeks after drug withdrawal. Each individual developing preovulatory yolk acts as its own pharmacokinetic compartment, with drug uptake and concentration independent of every other egg yolk compartment. Evaluating the pattern or duration of incurred residues in eggs based on the drug's half-life, as is done in domestic livestock, could expose the consumer to violative residues in eggs for an extended period of time. Utilization of our prediction model by producers or veterinarians would aid in making informed decisions of the components affecting residue duration in eggs and reduce the potential for unintentional contamination of this important food commodity.

Our laboratory's final area of research involves the important endeavor to develop methods to identify and quantitate contaminants in eggs. In recent years our laboratory, in collaboration with other FDA, the Department of Agriculture's Food Safety Inspection Service (FSIS) or Agricultural Research Service (ARS) laboratories have developed methods for arsenicals, sulfonamides, tetracyclines, beta-lactams, fluoroquinolones and pesticides. Without these methods, it is not possible for field personnel to monitor and alert our Agency about potential human food safety problems.

The author was CVM's 1996 nominee for the FDA Excellence in Laboratory Science Award, and would like to express his appreciation to Mr. Herman Hairston and Mr. Stuart Gaines for research and methods support and Ms. Mary Bartholomew for statistical and mathematical assistance with model development.