THE MERCK VETERINARY MANUAL
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Chemical Residues in Food and Fiber

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Veterinary drugs and pesticides are used routinely in animal production to manage diseases and control parasites, and crop protection chemicals are used in the production of animal feeds. It is possible, therefore, for foodstuffs of animal origin to be adulterated with residues of veterinary drugs and pesticides, and for animal fibers to be contaminated with pesticide residues. The veterinarian must consider the implications of both possibilities when providing for the health and welfare of animals. First, animals and animal products destined for human consumption must not contain residues of drugs or pesticides that exceed legally permitted concentrations. Second, pesticide residues in fiber have potential implications for public health, occupational health and safety, and environmental safety.

Chemical Residues in Foodstuffs of Animal Origin

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

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 veterinary medicines intended for administration to food-producing animals, an additional consideration is the safety of edible tissues and products (milk, eggs) derived from treated animals. Regulatory authorities establish maximum residue limits (MRL) or tolerances and set withdrawal times that ensure 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. Compliance with the national standards of importing countries becomes more difficult when the health standards, regulatory policies, and MRL-setting approaches of the exporting country and importing country differ. The situation is further 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.

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 tissues or products from 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 marker residue is the parent drug, its metabolites, or any combination of these, with a known relationship to the concentration of the total residue in the last tissue to deplete to the safe concentration. When the marker residue in the target tissue has depleted to the MRL, the total residue will have depleted to the safe concentration in all edible 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 each edible tissue from a treated 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 from a treated animal. Compliance with the preslaughter withdrawal time 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 is the most common cause of violative residues of veterinary drugs in food.

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 usually determined statistically, 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.

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 (more information can be obtained at http://www.fda.gov/AnimalVeterinary/Guidance ComplianceEnforcement). 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. Some of the pharmacokinetic principles as well as two practical examples that apply these principles are discussed see Residues Resulting from Veterinary Drugs, Medicated Feeds, or Application of Pesticides.

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. To determine hepatic clearance, for example:

where Q = blood flow and E = the extraction ratio. 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. For an IV-administered drug, the relationship is:

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.

If it is necessary to administer a veterinary drug to a healthy animal at twice the recommended rate, 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. However, if one is to administer a veterinary drug to an unhealthy animal with impaired drug excretion in which clearance is reduced by 50%, it can be seen from the relationship for half-life shown above 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.

The use of agricultural chemicals can result in residues in crops and pastures that 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. In all cases, chemical residues may result in the edible tissues, milk, or eggs derived from these animals.

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.

Chemical Residues in Animal Fibers

From an economic standpoint, the major animal fibers are wool and mohair. Although the primary focus of this section is pesticide residues in wool, many of the concepts discussed apply equally to mohair.

Flies, lice, keds, and mites adversely affect wool production and have animal welfare implications for the sheep industry. Ectoparasiticides have been the mainstay for managing infestations of these parasites in sheep flocks for many years. Two important manifestations of chemical application to sheep are the emergence of strains of parasites resistant to chemicals and the contamination of wool with pesticide residues. These two factors are linked because the application of pesticides to resistant strains of flies or lice increases the likelihood of treatment failure and the need to retreat later in the wool-growing season. Higher residues in both the wool on treated sheep and in harvested fleeces are possible consequences. Nonetheless, there are some situations in which late-season applications are justified on animal health and welfare or economic grounds. In view of community health and safety expectations and changing environmental standards, wool producers are seeking methods of managing external parasites on sheep that rely less on chemicals. Integrated pest management (IPM) approaches may involve various husbandry options such as shearing and crutching to combat flystrike; genetic improvements such as selecting against animals susceptible to fleece rot and flystrike; biologic and environmental controls such as the use of fly traps; and the selective use of chemicals.

Pesticide residues in wool are influenced by many factors, including the chemical and formulation used, the method of application, the rate and timing of the chemical application, and the length of wool at the time of application. (See alsodosage forms and delivery systems, p 2140.) The product types and chemical groups commonly used in the management of flies and lice on sheep include off-shears backline or spray-on products containing insect growth regulators (IGR), organophosphate pesticides (OP), and synthetic pyrethroid pesticides; short-wool plunge or shower dips that use IGR, magnesium fluorosilicate, OP, and spinosad; long-wool backline or spray-on products containing IGR; and long-wool jetting products containing IGR, macrocyclic lactones, OP, or spinosad. Wool producers must ensure that pesticides are applied in accordance with the label directions. With some chemicals, application to sheep with >6 wk wool growth results in unacceptably high residues remaining in wool to the next shearing. Repeat applications of pesticides may also result in higher wool residues at the next shearing, and backline products commonly leave higher residues at the site of application.

Although the use of sheep ectoparasiticides can result in significant chemical residues on treated wool, steps are taken that successfully mitigate any risk these residues may pose to public health. First, scouring removes residual pesticide from processed wool destined for the manufacture of woolen garments. Second, in the case of lanolin used in pharmaceuticals and cosmetics and as nipple emollients by nursing mothers, any residual pesticide associated with the wax component is removed during refining of the lanolin. Additional assurance regarding the quality of low-pesticide grades of lanolin is provided by compliance with the applicable regulatory standards.

With respect to occupational health and safety, residual pesticide in wool wax poses a hazard to shearers and other wool handlers during wool harvesting. For instance, nervous disorders and dermal irritation have allegedly occurred in shearers after shearing sheep treated with certain OP and synthetic pyrethroid (SP) pesticides, respectively. In addition, long-wool backline applications of SP pesticides can result in residue concentrations at the tips of backline staples high enough to cause dermal erythema in shearers and wool handlers. In Australia, such occupational health risks are managed by prescribing a sheep rehandling period in the product labeling. The sheep rehandling interval is the time that must elapse between the application of the ectoparasiticide and safely handling the treated animal. When sheep must be handled during the rehandling period, personal protective equipment should be used.

Chemical residues on treated wool may pose a risk to the environment when effluent is discharged during processing (eg, into rivers). This concern has necessitated the enactment of legislation to protect the environment. For some pesticides, environmental quality standards at concentrations that will not harm the most sensitive organisms in aquatic ecosystems have been established. In the EU, textile products are subject to eco-label requirements. In Australia, environmental risks posed by residues of ectoparasiticides on treated wool are mitigated by assigning a wool-harvesting interval (also referred to as a wool withholding period). The wool-harvesting interval is the time that must elapse before treated sheep may be shorn, ensuring that harvested wool meets the prescribed environmental residue limits.

The depletion of pesticide residues in wool has been mathematically modeled to predict the likely consequences of treatments at different times during the wool-growing season and to determine how late a pesticide may be applied to sheep without creating excessive residues at shearing. Modeling is a useful tool for determining wool-harvesting intervals and for assisting wool growers when choosing a pesticide and method of application. Test kits for quantifying pesticide residues in wool are also available.

Last full review/revision March 2012 by Philip T. Reeves, BVSc (Hons), PhD, FANZCVS

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