A Practical Approach, Second Edition=Ronald D. Ho.pdf

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CHAPTER 22Principles of Risk Assessment — FDA PerspectiveThomas F. X. Collins, Robert L. Sprando, Mary E. Shackelford, Marion F. Gruber, andDavid E. MorseCONTENTSI. Introduction and Background ............................................................................................878II. Food Safety ........................................................................................................................878A. Perspective .................................................................................................................878B. The Statutory Safety Standard for Additives ............................................................8791. Guidance for Food Additives ..............................................................................8802. Estimating Exposure to a Direct Food Additive.................................................8803. Safety Testing of a Food or Color Additive........................................................881III.Vaccine Safety....................................................................................................................890A. Perspective .................................................................................................................890B. General Considerations..............................................................................................891C. Specific Considerations .............................................................................................8911. Animal Models ....................................................................................................8912. Dose .....................................................................................................................8923. Immunization Interval .........................................................................................8924. Exposure Period and Follow-Up Period .............................................................8925. Study Endpoints...................................................................................................892D. Summary Remarks ....................................................................................................893IV. Drug Safety ........................................................................................................................893A. Perspective .................................................................................................................893B. Product Labels ...........................................................................................................893C. Pregnancy Labeling — <strong>Practical</strong> Considerations......................................................894D. Assessment of Reproductive and Developmental Toxicity ......................................8941. Nonclinical Reproductive Toxicity Data Assessment — Future ........................8952. Data Needed for the Integration Process ............................................................8953. Types of Reproductive and Developmental Toxicity Evaluated.........................8954. The Integration Process .......................................................................................8965. Section A. Overall Decision Tree Applicable to All Data-Sets..........................8966. Section B. No Signal (Applicable to Data-sets without Evidenceof Reproductive or Developmental Toxicity)......................................................8987. Section C. Applicable to Data-sets with One or More Positive Indicationsof Reproductive or Developmental Toxicity ......................................................900877© 2006 by Taylor & Francis Group, LLC
878 DEVELOPMENTAL REPRODUCTIVE TOXICOLOGY: A PRACTICAL APPROACH, SECOND EDITION8. Factor 1. Signal Strength, Part I..........................................................................9009. Factor 2. Signal Strength, Part II ........................................................................90210. Factor 3. Pharmacodynamics...............................................................................90311. Factor 4. Concordance between the Test Species and Humans .........................90412. Factor 5. Relative Exposures...............................................................................90513. Factor 6. Class Alerts ..........................................................................................90614. Summary and Integration of Positive Findings ..................................................906Acknowledgments..........................................................................................................................907References ......................................................................................................................................907I. INTRODUCTION AND BACKGROUNDThe mission of the Food and Drug Administration (FDA) is “to promote and protect the publichealth by helping safe and effective products reach the market in a timely way, and monitoringproducts for continued safety after they are in use” (http://www.fda.gov). The FDA thus regulatesa multitude of diverse consumer products.Five centers within the FDA are responsible for regulating the use of a wide range of productsfor humans and animals. For humans, the safety of food is regulated by the Center for Food Safetyand Applied Nutrition (CFSAN) (excluding meat and poultry products regulated by the U.S.Department of Agriculture). Human drugs used for the treatment and prevention of disease areregulated by the Center for Drug Evaluation and Research (CDER). Biologics (a category thatincludes vaccines, blood products, biotechnology products, and gene therapy) are regulated by theCenter for Biologics Evaluation and Research (CBER). Medical devices (a category that includesitems that range from simple tongue depressors to complex items such as pacemakers and dialysismachines) are regulated by the Center for Devices and Radiological Health. The Center forVeterinary Medicine at FDA regulates drugs and devices used for animals (pets and also animalsthat produce food). Before manufacturers can market animal drugs, they must obtain FDA approvalby providing proof of their safety and effectiveness. Livestock drugs are also evaluated for theirsafety to the environment and to the people who eat the animal products. Of the many productsregulated by the FDA, only human food additives (regulated by CFSAN), drugs (regulated byCDER), and vaccines (regulated by CBER) are discussed here. The emphasis is on how reproductiveand developmental toxicity studies are utilized in risk assessment at the FDA. The chapter reflectsthe complexity of the utilization of these studies within the agency.A. PerspectiveII. FOOD SAFETYFood safety in the United States is intricately interwoven with legal decisions. From the mid-1800sto the early 1900s, use of chemical preservatives and toxic colors in foods was virtually uncontrolled.In 1938, Congress passed the Federal Food, Drug, and Cosmetic Act (FFDCA). Although imperfect,the law provided some measure of food safety. Some of the provisions were: poisonous substancescould no longer be added to foods except where unavoidable or required in production; factoriescould be inspected; food standards were required to be set up when needed in the interest ofconsumers; legal remedies against violations included Federal court injunctions.During the 1940s and early 1950s, with the increased needs of World War II and rapid advancesin chemical and food technology, many new food additives were introduced by the food industry.Congress and the general public began to be concerned and to ask questions about the safety ofsome of the additives. The Pesticide Amendments of 1956 were the first Congressional actions© 2006 by Taylor & Francis Group, LLC
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Second EditionDEVELOPMENTALandREPRO
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Published in 2006 byCRC PressTaylor
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Chapter 12Chapter 13Chapter 14Chapt
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The EditorRonald D. Hood, Ph.D., is
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Alan M. HobermanArgus ResearchHorsh
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APPENDIX ATerminology of Anatomical
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TERMINOLOGY OF ANATOMICAL DEFECTS 9
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Organ/StructureCodeNumberObservatio
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Organ/Structure10145 Ocular colobom
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Organ/StructurePulmonaryarteryPulmo
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Terminology of developmental abnorm
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Organ/StructureCervicalcentrumCodeN
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Organ/Structure10689 Misshapen thor
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Organ/StructureSacralcentrumSacralv
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968 DEVELOPMENTAL REPRODUCTIVE TOXI
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1000 DEVELOPMENTAL REPRODUCTIVE TOX
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Table 1Human Non-human Primate Rat
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Table 1 (continued)Sertoli CellsHum
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Table 2 (continued) Landmarks in th
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Table 2 (continued) Landmarks in th
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POSTNATAL DEVELOPMENTAL MILESTONES
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PART IPrinciples and Mechanisms© 2
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4 DEVELOPMENTAL REPRODUCTIVE TOXICO
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10 DEVELOPMENTAL REPRODUCTIVE TOXIC
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Table 2.6Receptor(Official Name a )
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Clearly, more research needs to be
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CHAPTER 6Comparative Features of Ve
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COMPARATIVE FEATURES OF VERTEBRATE
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Table 6.2Comparative reproductive a
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Maturation andRelease ofGametesSper
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Amniotic cavity 9.5 1.5 1-4 1-4,6,9
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Posteriorcardinal veinsestablishedT
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PosteriorcardinaldegenerationRight
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StomachappearsThirdpharyngealpouch;
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Table 6.6DescriptionComparative ges
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ParathyroidParathyroids 12.5 6.2 41
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Table 6.8DescriptionComparative ges
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Formation ofchoroid plexusof latera
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Optic nervefibers presentDifferenti
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Table 6.10DescriptionMuscular Syste
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Distalphalanges offingersseparatedF
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Table 6.11DescriptionIntermediateme
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Table 6.12DescriptionComparative ge
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CHAPTER 7Developmental Toxicity Tes
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DEVELOPMENTAL TOXICITY TESTING —
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Female 0.00-0.69 0.004-0.39 0.00-0.
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Figure 8.11775Pott DescribesScrotal
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The underlying physiology of juveni
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Table 8.5Total body composition by
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Table 8.6Serum chemistry values for
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Table 8.7Parameter bHematology valu
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CHAPTER 9Significance, Reliability,
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DEVELOPMENTAL AND REPRODUCTIVE TOXI
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Prior to the early 1980s, numerous
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Figure 9.51906Food andDrugs Act2000
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Table 9.18Selected comparison point
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Table 9.33Selected comparison point
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Table 9.48What do regulatorswant to
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CHAPTER 10Testing for Reproductive
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TESTING FOR REPRODUCTIVE TOXICITY 4
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We would like to acknowledge the ef
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CHAPTER 12Role of Xenobiotic Metabo
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ROLE OF XENOBIOTIC METABOLISM IN DE
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y ESR spectrometry. 122 Further ESR
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CHAPTER 13Use of Toxicokinetics in
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USE OF TOXICOKINETICS IN DEVELOPMEN
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CHAPTER 17Statistical Analysis for
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STATISTICAL ANALYSIS FOR DEVELOPMEN
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CHAPTER 19Perspectives on the Devel
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PERSPECTIVES ON THE DEVELOPMENTAL A
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Guideline OECD 415 (One Generation)
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The Office of Prevention, Pesticide
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CHAPTER 20Human Studies — Epidemi
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HUMAN STUDIES 801I. INTRODUCTIONEpi
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HUMAN STUDIES 803is actively trying
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HUMAN STUDIES 805100908070Induced a
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HUMAN STUDIES 8071009590>37 w33-36
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HUMAN STUDIES 811from monstrous, us
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HUMAN STUDIES 815G. Childhood Cance
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HUMAN STUDIES 817( P1- P2) f ( 1 -
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