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

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362 DEVELOPMENTAL REPRODUCTIVE TOXICOLOGY: A PRACTICAL APPROACH, SECOND EDITIONA. Guideline RequirementsTable 9.18 presents selected differences in study design requirements between various agencyguidelines. The OPPTS of the EPA has produced prenatal developmental toxicity testing guidelinesfor use in the testing of pesticides and toxic substances. This guidance document harmonized thepreviously separate testing requirements under TSCA and FIFRA. The OECD and the JapaneseMinistry for Agriculture, Forestry and Fisheries (MAFF) have developed guidelines very similarto those of the EPA. For medicinal products, the ICH developed technical requirements for theconduct of developmental toxicity studies in support of pharmaceutical products registration forthe European Union, Japan, and the United States. For food ingredients, the Center for Food Safety& Applied Nutrition (CFSAN) within the FDA has developed guidelines for developmental toxicitystudies. Finally, the Maternal Immunization Working Group of the Center for Biologics Evaluationand Research (CBER) at the FDA has developed a draft guidance document for developmentaltoxicity studies of vaccines.1. Animal ModelsRelevance of the mode of action of the test agent, when known, is the most important factor in thechoice of animal models for developmental toxicity testing, regardless of guideline requirements.Developmental toxicity studies are typically performed in two species, one rodent and one nonrodent.Historically, the rat and rabbit have been the preferred rodent and nonrodent species, respectively,for these types of studies. However, alternatives to these species exist (refer to Section III.Bof this chapter for further details).A recent publication has proposed the use of a tiered approach to developmental toxicity testingfor veterinary pharmaceutical products for food-producing animals. 61 Using this approach, if teratogenicitywere to be observed in the rodent, no testing in a second species would be required.However, if a negative or equivocal result for teratogenicity were to be observed in the rodent, thentesting in a second species, preferably the rabbit, would be conducted.In special cases, investigators may use the dog or nonhuman primate model in lieu of the rabbit.However, the cost of these models and the need for specialized techniques and experience to conducta successful study necessitate a well-articulated, scientific rationale justifying their use.An example of effective use of the canine model in developmental toxicology was a series ofstudies performed with a hemoglobin-based oxygen carrier (HBOC) intended to be an oxygenbridge in lieu of human blood transfusion. A preliminary developmental toxicity study in the ratrevealed significant embryo toxicity (lethality, growth retardation, and structural malformations inmultiple organ systems) following infusion of the test article on GD 9. 62 These effects coincidedwith the prechorioallantoic placental period of development when histiotrophic nutrition via theinverted visceral yolk sac placenta (InvYSP) is essential to development in rodents. The results ofthe preliminary study led to the hypothesis that the embryo toxicity in the rat was unique to thepresence of the InvYSP during the time the malformations were occurring, and that these findingsrepresented a false positive signal for human developmental toxicity. 63 Subsequent rat whole-embryoculture studies confirmed a pronounced effect on endocytotic and proteolytic functions in thevisceral yolk sac placenta. Because the canine model and humans do not possess an InvYSP, aseries of phased-exposure studies in the dog was conducted. The results of the canine studiesrevealed no evidence of developmental toxicity, substantiating the hypothesis. 622. Timing and Duration of TreatmentOf particular note in the comparison of developmental toxicity study guidelines is the differencebetween EPA and ICH requirements for the timing and duration of treatment. The EPA guidelinesrequire dose administration throughout the period of prenatal organogenesis (beginning at implantation© 2006 by Taylor & Francis Group, LLC
Table 9.18Selected comparison points between various regulatory agency guideline requirements for developmental toxicity studiesFDA/Redbook 2000 FDA/Vaccines a Japan/MAFFEPA (1998) ICH (1994) OECD (2001) (2000 Draft) (2000 Draft) (1985)Ref. 166 167 168 169 170 171Choice of animal model Rat and rabbit Rat and rabbit Rat and rabbit Rat and rabbit Vaccine should elicit Rat and rabbitimmune responseSingle or multiple Multiple Multiple Multiple Multiple Single MultiplespeciesRandomization Yes Yes Yes Yes Yes Not mentionedGroup SizeRodentsApprox. 20 females withimplants at necropsy16–20 litters Approx. 20 females withimplants at necropsyApprox. 20 females withimplants at necropsy16–20 litters per phase At least 20 pregnantfemalesNonrodentsApprox. 20 females withimplants at necropsy16–20 litters Approx. 20 females withimplants at necropsyApprox. 20 females withimplants at necropsy16–20 litters per phase At least 12 pregnantfemalesTiming and duration oftreatment/ExposurePeriod of majororganogenesis bImplantation to closure ofhard palatePrior to mating andimplantation to birthPeriod of majororganogenesisMorphologic examinationof fetuses cRodentsNonrodentsApprox. 1/2 of each litterfor skeletal alterations(preferably bone andcartilage)Remaining fetuses fromeach litter for soft tissuealterations (acceptableto examine all fetusesviscerally followed byskeletal examination)All fetuses for both softtissue and skeletalanomalies (capita of 1/2removed and evaluatedinternally, thusprecluding skeletalexamination of thosecapita)1/2 of each litter forskeletal alterationsRemaining fetuses fromeach litter for soft tissuealterationsEach fetus for soft tissue(by dissection) andskeletal anomaliesImplantation to day priorto scheduledlaparohysterectomy bApprox. 1/2 of each litterfor skeletal alterationsRemaining fetuses fromeach litter for soft tissuealterationsAll fetuses for both softtissue and skeletalanomalies (capita of 1/2removed and evaluatedinternally, thusprecluding skeletalexamination of thosecapita)Implantation to day priorto scheduledlaparohysterectomy bApprox. 1/2 of each litterfor skeletal alterationsRemaining fetuses fromeach litter for soft tissuealterations (acceptableto examine all fetusesviscerally followed byskeletal examination)All fetuses for both softtissue and skeletalanomalies (capita of 1/2removed and evaluatedinternally, thusprecluding skeletalexamination of thosecapita)1/2 of each litter forskeletal alterationsRemaining fetuses fromeach litter for soft tissuealterationsEach fetus for soft tissue(by dissection) andskeletal anomalies1/3 to 1/2 of each litter forskeletal alterationsRemaining fetuses fromeach litter for soft tissuealterationsEach fetus for soft tissue(by dissection) andskeletal anomaliesaThe FDA guidelines for developmental toxicity studies of vaccines also include a requirement for a follow-up phase from birth to weaning for evaluation of effects on preweaningdevelopment and growth, survival, developmental landmarks, and functional maturation.bIf preliminary studies do not indicate a high potential for preimplantation loss, treatment in the de nitive study may include the entire period of gestation (typically gestational days 0–20for rats and 0–29 for rabbits).cICH guidelines do not require examination of the low- and middose fetuses for soft tissue and skeletal alterations where evaluation of the control and high-dose animals did not revealany relevant ndings .DEVELOPMENTAL AND REPRODUCTIVE TOXICITY STUDY FINDINGS 363© 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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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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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 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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CHAPTER 21Developmental and Reprodu
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