Chapter 2
Use of Xenobiotics in Food-Producing Animals in the United States Regulatory Aspects
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Ν.
E.
Weber
Division of Chemistry, Center for Veterinary Medicine, Food and Drug Administration, Rockville,MD20855 A FEDERAL REGISTER document published December 31, 1987 permits the use of carcinogenic animal drugs in food animals as allowed by the DES proviso to the Delaney Clause found in the Food, Drug and Cosmetic Act. A set of guidelines was developed to support the regulation. This chapter will explain the significant toxicology and chemistry elements of those guidelines including metabolic and kinetic aspects that are employed in the regulation of carcinogenic as well as non-carcinogenic animal drugs and feed additives. This report is designed to give the reader an overview of the regulation of veterinary drugs in the United States. Particular emphasis will be given to the human food safety aspects after the other parts of the regulatory process are outlined so that a broadened perspective of the regulatory scheme may be seen. A profile of regulation of veterinary drugs includes not only the awareness of the need to demonstrate the efficacy of the drug and human food safety aspects but also the aspects of target animal safety, environmental safety and manufacturing controls. Since the animal drug amendments of 1968, veterinary drugs have had their own section of the Code of Federal Regulations (CFR), section 512. Under this section the sponsor of a new animal drug is required to demonstrate not only the efficacy of the drug, but also the safety to the target animal. These studies must be scientifically valid and well controlled to support the approval and are codified in 21 CFR 514. Before continuing on to the human food safety and environmental portions, mention should be made that there is a large amount of information required concerning the manufacture and controls for production of the drug prior to its approval. These requirements are very similar if not identical to those for human drugs. The manufacturer must comply with good manufacturing practices (GMPs) and have acceptable stability tests for the product both prior to as well as after the approval. Environmental Issues Under the National Environmental Policy Act (ΝΕΡΑ) of 1969, the Center for Veterinary Medicine must consider the potential environmental impact of the actions (decisions) that it takes. The types of action that most commonlyrequirean environmental evaluation are
This chapter not subject to U.S. copyright Published 1992 American Chemical Society Hutson et al.; Xenobiotics and Food-Producing Animals ACS Symposium Series; American Chemical Society: Washington, DC, 1992.
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XENOBIOTICS AND FOOD-PRODUCING ANIMALS
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authorizations to investigate uses of new animal drugs and approvals of new animal drugs for marketing. The environmental evaluation of the impact of these actions (and most others) can take one of three forms: (i) a categorical exclusion from preparing an environmental assessment, (ii) an environmental assessment (EA) and (iii) an environmental impact statement (EIS). The procedures and reports needed to address the environmental issues are described in Title 21 Part 25 of the Code of Federal Regulations (CFR). There is a significant amount of documentation needed to support each of the forms identified above. That documentation usually consists of describing the specific action, describing any controls used to limit the release of the animal drug into the environment and, as necessary, providing information concerning the potential fate and effects of the animal drug in the environment. Often information from the drug metabolism studies used to determine food residue chemistry as well as results of toxicology studies used to determine human food safety can be used as part of the fate and effects information needed to evaluate the potential environmental impact of a new animal drug. The latter also includes safety to the persons who handle and administer as well as produce the drug. The Environmental Sciences Staff at the Center for Veterinary Medicine, FDA, reviews the information submitted. Human Food Safety The remainder of this article will outline the major parts of the human food safety portion of the new animal drug approval process with emphasis on the important interface between drug toxicology and residue chemistry. However, before the discussion of the guideline material a brief discussion of some important historical aspects and definitions needs to be given. Residue. To begin, the definition of a residue has been around for a long time. One of the definitions of a residue comesfromthe 1958 food additive amendments of the Federal Food, Drug, and Cosmetic Act (FFD&CA), As Amended (/), Sec. 409. This section addresses residues from the standpoint of methods as well as safety as follows: (b) (2)(D) a description of practicable methods for determining the quantity of such additive in or on food and any substance formed in or on food, because of its use; (c) (5)(A) the probable consumption of the additive and of any substance formed in or on food because of the use of the additive; Time has not signiflcandy changed the definition of a residue. A recent definition that was given in a FDA 1985 proposed regulation (2) is: "Residue" means any compound present in edibletissuesof the target animal that results from the use of the sponsored compound, including the sponsored compound, its metabolites, and any other substances formed in or on food because of the sponsored compound's use. The phrase "drug residues" is used synonymously with residue. The concepts apply whether the residue comes from an animal drug or feed additive. Another way of visualizing drug residues is seen in the following outline.
Hutson et al.; Xenobiotics and Food-Producing Animals ACS Symposium Series; American Chemical Society: Washington, DC, 1992.
2.
WEBER
Use of Xenobiotics in Food-Producing Animals in the U.S.
19
DRUG RESIDUES 1. Parent compound 2. Metabolites- addition,cleavage, oxidation, reduction of functional groups 3. Conjugates- small molecules (glucuronides, etc.) macromolecules (bound residues)
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Origin of No Residue. The 1958 amendments also had another important food safety concept, the anticancer proviso or the Delaney Amendment as it is often referred to. This provision is incorporated in Section 409 (c)(3)(A) and states "That no additive shall be deemed safe if it is found to induce cancer when ingested by man or animal or if it is found, after tests which are appropriate for the evaluation of the safety of food additives, to induce cancer in man or animal." In 1962, section 409 of the FFD&CA was amended, in which the same section, (c)(3)(A), quoted above now was given additional language that exempted feed additives through the so called DES PROVISO by stating after the above wording "that this proviso shall not apply with respect to the use of a substance as an ingredient of feed for animals which are raised for food production, if the Secretary finds (i) that, under the proposed conditions of use ...such additive will not adversely affect the animals... and (ii) that no residue of the additive will be found (by methods of examination prescribed or approved by the Secretary ...) in any edible portion of such animal after slaughter or in any food yielded or derived from the living animal." When the FFD&C Act was amended in 1968 to include a new section (Section 512) on New Animal Drugs, the wording of the DES Proviso was included in that section, Sec. 512 (d)(1)(H). The SOM Procedure. The no residue wording of the DES Proviso which states "...no residue by a method prescribed or approved by the Secretary..." became the foundation by which FDA regulates not only carcinogenic but also non-carcinogenic animal drugs. Beginning in 1973 and continuing for a period of 14 years, the FDA attempted to finalize a regulation to implement the concept by which carcinogenic animal drugs could be approved. The final regulation was published on December 31,1987 (J). The title of the rule is "Sponsored Compounds in Food- Producing Animals; Criteria and Procedures for Evaluating the Safety of Carcinogenic Residues; Final Rule." However, it has become known as the Sensitivity of the Method (SOM) document because it is based on the concept that the Secretary prescribes or approves the methods for carcinogens as permitted by the DES Proviso and through a process determines the level (sensitivity/concentration) required for no residue. A scientific principle applied is that once a drug is given to an animal, residues will not deplete to absolute zero. The focal point of the SOM rule became the procedure by which no residue is determined The regulation uses a simple approach which basically involves extrapolating cancer data from laboratory animal models (usually mice or rats) from the observed natural or background incidence to a predicted increased incidence of no more than 1 tumor in 1 million test animals as a result of ingesting the sponsored compound. These calculations involve the number of animals with tumors compared to the total number of animals exposed at a dose in their diet over a lifetime. Various mathematical models are discussed for calculating the 1 in 1 million dose. However, the FDA preferred the multistage model (4) at thetimethe final rule was written. The 1 in 1 million dose becomes the permitted concentration that is used to calculate the no residue level required for the method of analysis for residues in food for human consumption. Although this value is involved in the calculation, an additional calculation is needed to take into consideration total residues in the food animal before a specific value for a specific analyte can become the no residue value by which the drug is regulated. In the following paragraphs, the procedure by which this is done will be outlined. Hutson et al.; Xenobiotics and Food-Producing Animals ACS Symposium Series; American Chemical Society: Washington, DC, 1992.
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XENOBIOTICS AND FOOD-PRODUCING ANIMALS
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Carcinogenic Residues and General Food Safety - A Unified Concept The SOM concept became fully integrated into a general food safety concept that the FDA had developed throughout most of the period prior to the publication of the final rule. FDA uses a similar chemistry approach for determining the tolerance for residues for any compound including "no residue" for a carcinogen. The unified concept applies to carcinogens and non-carcinogens. Before the carcinogenicity of a compound can be evaluated, all compounds have to be treated similarly to assess their carcinogenic potential. An initial decision tree approach that all compounds must undergo was outlined in the SOM document Threshold Assessment is the name given to this process. The process initially involves a structure-activity assessment to determine whether the sponsored compound is a suspect carcinogen. The compound must also be tested in a battery of mutagenicity tests and must tested in subchronic 90 day studies-usually in the rat and dog. The carcinogenic potential of the compound may be suggested by these tests. If any of the tests signal a potential for carcinogenicity, then chronic lifetime studies are required. When a carcinogenic potential is not seen, the level of residue in edibletissuesfurther determines whether a sponsored compound has to undergo chronic studies. Threshold assessment is outlined below to show the interaction of its elements. Categories D and C refer to suspect and non-suspect carcinogens respectively based on structure-activity relationships. Assignment of category A or Β resultsfromthe outcome of biological tests which include the mutagenesis battery described below and 90 day subchronic studies in laboratory animals. General Food Safety (GFS) is the category into which a compound is placed when it is determined not to be a carcinogen. The calculation of a safe concentration for residues for GFS is discussed later. DRUG Structure Activity
(Suspect) Biology
C (Non-suspect)
+
—I CHRONIC STUDIES
Xs Use Level
LOW ,250ppb
LiGH
,>10ppb
CHRONIC STUDIES
liGH
,
