Chemical Residues in Foodstuffs of Animal Origin

Residues Resulting from Veterinary Drugs, Medicated Feeds, or Application of Pesticides

Residues Resulting from Consumption of Stockfeeds Treated with Agricultural Chemicals

Chemical residues may be found in animal tissues, milk, or eggs following the administration of veterinary drugs and medicated premixes, the application of pesticides to animals, or the consumption of stockfeeds previously treated with agricultural chemicals.

Residues Resulting from Veterinary Drugs, Medicated Feeds, or Application of Pesticides:

Extensive regulatory and monitoring systems have been established to ensure that chemical residues in food do not constitute an unacceptable health risk. The premarket approval process undertaken by regulatory authorities for new veterinary drugs and medicated feeds evaluates the quality, safety, and efficacy of these products. For those veterinary medicines intended for administration to food-producing animals, an additional consideration is the safety of products derived from treated animals for human consumption. Maximum residue limits (MRL) or tolerances are established, and withdrawal times are set in a manner that ensures residues of the active constituent will not exceed the MRL when the label instructions for the product are followed.

Residue programs consist of 2 principal activities: monitoring and surveillance. Residue-monitoring programs randomly sample tissues from animals at slaughter. Tissue samples are assayed for residues of specific veterinary drugs, pesticides, and environmental contaminants, and the residues are assessed for compliance with the applicable MRL or environmental standard. The sample size chosen for monitoring purposes typically provides a 95% probability of detecting at least 1 violation when 1% of the animal population contains residues above the MRL. Surveillance programs, by comparison, sample tissues from animals suspected of violative residues on the basis of clinical signs or herd history. Animals identified with violative residues of veterinary drugs or pesticides do not enter the food chain.

Residue monitoring is also a trade requirement, either mandatory or as an expectation, of importing countries allowing market access to food products derived from animals. Governments adopt health standards, regulatory policies, and MRL-setting approaches that may differ between countries. The situation is often exacerbated when patterns of use differ across countries or where the minor status of a disease or pest in a country does not warrant product registration, in which case MRL are unlikely to be established. In addition to confounding international trade by requiring exporting countries to comply with a diverse range of standards imposed by importing countries, differing national standards may have implications for the protection of public health.

Regulatory authorities undertake premarket approval assessments of applications in support of new veterinary drugs and medicated feeds. These assessments consider scientific data submitted by the sponsor. In the case of veterinary medicines proposed for use in food-producing animals, the data must demonstrate the safety of any residues remaining in the edible products of treated animals. These data describe the compound’s toxicology, metabolism, pharmacokinetics, residue depletion, and dietary exposure. The key parameters derived in the safety and residue evaluations are defined below.

The acceptable daily intake (ADI) is the amount of a veterinary drug, expressed on a body weight basis, that can be ingested daily over a lifetime without an appreciable risk to human health. The ADI is established based on a review of animal studies on toxicologic, pharmacologic, or microbiologic effects as appropriate. Conservative safety factors are built into the ADI.

The safe concentration is the maximal allowable concentration of total residues of toxicologic concern in edible tissue. The safe concentration is calculated from the ADI and considers the weight of an average person and the amount of meat, milk, or eggs consumed daily by a high-consuming individual.

An MRL or tolerance is the maximal concentration of residue resulting from the use of a veterinary drug (expressed in mg/kg or µg/kg on a fresh-weight basis) that is legally permitted as acceptable in or on a food. It is based on the type and amount of residue considered to be without any toxicologic hazard for human health as expressed by the ADI. Other relevant public risks and aspects relating to food technology, good practice in the use of veterinary drugs, and analytical methodologies are also considered when establishing MRL.

The concentration of the marker residue decreases in a known relationship to the level of total residues in tissues, eggs, milk, or other animal tissues.

The target tissue is the edible tissue with residues that deplete to a concentration below the MRL at a slower rate compared with other edible tissues. It is considered suitable for monitoring compliance with the MRL of the whole carcass of the animal. The target tissue is frequently liver or kidney for the purpose of domestic monitoring and muscle or fat for monitoring meat or carcasses in international trade.

The withdrawal time is the period of time between the last administration of a drug and the collection of edible tissue or products from a treated animal that ensures the total residues deplete to below the safe concentration, and the marker residue depletes to below the MRL. Failure to observe the correct withdrawal time for the drug is the most common cause of violative residues of veterinary drugs in food. To ensure that withdrawal times are observed, the veterinarian must understand the clinical utility of withdrawal times in product labeling and the pharmacokinetic basis of assigning a significantly extended withdrawal time when treating certain unhealthy animals or when using veterinary drugs extra-label.

Regulatory authorities determine withdrawal times on the basis of residue depletion data generated using healthy animals representative of those normally treated with the product. The drug formulation used in these trials is identical to the market formulation, which is administered at the maximal label rate. The withdrawal time is determined using a statistical approach, taking into account variability among animals in drug disposition.

Unlike an MRL, which applies to a veterinary drug regardless of the dosage form, route of administration, or dosage regimen, the withdrawal time stated in the product labeling applies only to that particular formulation when administered by the recommended route and in accordance with the dosage regimen. Alteration to any of these factors modifies the pharmacokinetic behavior of the drug in the animal and invalidates the withdrawal time. In addition, a range of physiologic and pathologic factors may modify the drug’s disposition in the animal and prolong its elimination. The withdrawal time in the product labeling, which is based on studies in healthy animals, is likely to underestimate the time required for residues to decline below the MRL in these situations.

In the USA, some veterinary or human drugs can be used extra-label (off-label) in food-producing animals under the Animal Medicinal Drug Use Clarification Act, provided certain conditions are met. The veterinarian must be mindful, however, that the extra-label use of a small number of veterinary drugs is prohibited by the FDA. Extra-label use refers to use in a species not included in the product labeling or at a dosage rate higher than those stated in the product labeling. For drugs used in this manner, data are inadequate to demonstrate the safety of food products derived from the treated animal. An understanding of pharmacokinetic principles allows extended withdrawal times to be estimated both when veterinary drugs are used in an extra-label manner and in situations that may lead to changes in the kinetic behavior of a drug in an individual animal.

The elimination half-life is the time required for the concentration of a drug to be reduced by 50%. It follows that 99.9% of an administered dose is eliminated over 10 half-lives. In food-producing animals, the residues of drugs with longer terminal elimination half-lives take longer to deplete to below the MRL. The pharmacokinetic behavior of the drug determines if the elimination half-life in tissues will exceed the elimination half-life in plasma. In food-producing animals, the terminal elimination half-life for the slow elimination phase, or γ phase, of the residue concentration versus time profile determines the withdrawal time. Half-life is determined by both clearance (Cl) and volume of distribution (Vd) as shown by the relationship:

Clearance is the blood volume cleared of drug per unit time and refers to the irreversible elimination of a drug from the body. The principal organs of elimination are the liver and kidneys; organ clearance is related to blood flow and the efficiency of drug removal. Factors that affect hepatic clearance include hepatic function, hepatic microsomal enzyme activity, and hepatic blood flow.

Volume of distribution relates the amount of drug in the body to the concentration of drug in plasma according to the relationship: Vd is a characteristic property of the drug rather than the biologic system. A drug confined to the vascular compartment has a minimal value of Vd equal to plasma volume. Factors influencing Vd include the size of the drug molecule, lipid solubility, drug pKa, and tissue blood flow. Certain disease states effect changes in volume of distribution for a drug, and changes in drug binding, in particular, usually alter Vd.

The following examples demonstrate the use of these pharmacokinetic principles to estimate an extended withdrawal time: 1) Administration of a veterinary drug to a healthy animal at twice the recommended rate—in this situation, the elimination half-life of the drug is unchanged. Assuming the pharmacokinetic behavior of the drug demonstrates first-order kinetics, which is generally the case, doubling the administered dose will increase the depletion time by one half-life. Thus, the withdrawal time should be extended by one half-life to arrive at the same concentration as observed for the recommended rate. 2) Administration of a veterinary drug to an unhealthy animal with impaired drug excretion in which clearance is reduced by 50%—from the relationship for half-life shown above, it can be seen that reducing clearance by 50% will double the half-life. Accordingly, the withdrawal time should be doubled to arrive at the same concentration as observed for an animal with a fully functional drug excretory system.

The predicted result should always be verified using a rapid-screening test. The detection of residues is likely to signal that the withdrawal time should be extended and the rapid-screening test repeated.

Residues Resulting from Consumption of Stockfeeds Treated with Agricultural Chemicals:

The use of agricultural chemicals can result in residues in crops and pastures, which are subsequently consumed by animals. During drought conditions, the feeding of potentially contaminated crop byproducts, such as stubbles and fodder, and processed fractions, including grape marc, citrus pulp, fruit pomace, and cannery wastes, is likely to become more prevalent. Chemical residues may be found in animal tissues, milk, or eggs in all cases. For approved uses of crop protection chemicals that are likely to result in dietary exposure of food-producing animals, regulatory authorities establish animal commodity MRL. The approach adopted for establishing these MRL is fundamentally different from the one that applies to veterinary drugs. Animal transfer studies, which allow determination of the relationship between the level of chemical in the animal diet and the concentration of residue found in edible tissues, milk, and eggs, are pivotal in determining MRL. MRL for animal tissues, milk, and eggs are established at concentrations that cover the highest residues expected to be found from the estimated livestock dietary exposure. Human dietary exposure assessments are also performed to verify that food complying with MRL is safe for consumption. In animal production systems, compliance with animal commodity MRL relies on adherence to a stipulated period to allow residues in the crop to deplete prior to the commencement of animal feeding, a stipulated period to allow residues in the animal to deplete prior to slaughter, or a combination of both.