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

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NONCLINICAL JUVENILE TOXICITY TESTING 2811. General Toxicity ScreenThe term “general toxicity screen” suggests that basic toxicity endpoints, such as clinical observations,body weight, food consumption, clinical pathology, and histopathology will be evaluated;however, these studies may encompass additional endpoints. While growth and pathology endpointsplay a key role in the general toxicity screening study, they may be accompanied by more specializedevaluations, including assessments of reproductive performance, behavior, and immune competence.These study designs often initiate dose administration prior to or at the time of weaning,and measure growth and development into young adulthood. Typically, these studies are conductedin rodents and require many animals to address relevant concerns. <strong>Ho</strong>wever, it is not uncommonfor these studies to be conducted in large animal models. A large animal model provides someadvantages over the rodent, including the capability of longitudinal assessments of various physiologicalendpoints. The general toxicity screen also commonly includes a posttreatment (or recovery)period, in which persistent and/or latent effects of the test article can be examined in comparisonto changes observed during treatment. An example of one such study design (the within-litter studydesign) is illustrated in Figure 8.7.The general toxicity screen serves an important purpose in the nonclinical juvenile study batterybecause it may reveal target organs not identified in adult toxicity studies. In addition, the generaltoxicity screen may serve to highlight areas that require further research to define the mode ofaction of the test article.2. Adapted Adult Toxicity StudyFor the purposes of this chapter, the authors define an adapted adult toxicity study to be areproductive toxicity study in which the design is modified to include a satellite juvenile phase(e.g., immunotoxicity, neurotoxicity, endocrine modulation screen, comet assay, or brain morphometricassessment). For some chemicals, the adapted adult design may be sufficient to addresspediatric concerns in lieu of conducting a general toxicity screen. These modified studies have theadvantage of a transgenerational exposure regimen, wherein the parental population is first exposed,followed by exposure of the juvenile population (either with or without concurrent parental exposure);this exposure model may more closely parallel the real-world situation for some chemicals.For example, the design for a two-generation reproductive toxicity study required by the EPA andthe OECD encompasses a 10-week premating exposure period that begins, for the F 1 generation,immediately following weaning. 55,100 During this period, growth and sexual developmental landmarksare evaluated. If there is concern that the infant and/or toddler may be directly exposed tothe test article, appropriate adjustments to the onset of dose administration for the F 1 generationmay be considered. The adjustments may consist of oral intubation of the offspring (in a studywhere administration is by gavage), modified feeding canisters (see Figure 8.8 for a diagrammaticrepresentation of a Lexan ® rat creep feeder) that would allow measurement of whole-litter offspringfood consumption (in a study where administration is via the diet), or specially designed inhalationchambers that allow litters to be exposed concurrently with dams (Figure 8.9). In the same way,for some pre- and postnatal development studies, concerns over the bioavailability of the test articlein the neonate dictate that a modified approach for dose administration must be used. For thesesituations, pharmaceutical companies have developed a strategy wherein maternal animals areadministered the test article during gestation, followed by a combination of maternal and offspringdose administration during the postnatal period.In cases where inadequate offspring exposure has been demonstrated following delivered dosesto the dam only, both the EPA and OECD have requested modifications to the developmentalneurotoxicity study design to incorporate direct administration of the test article to the F 1 offspringprior to weaning. 52,167 These requests have been made to the registrants for certain classes ofcompounds and reflect heightened public concern for special populations at risk.© 2006 by Taylor & Francis Group, LLC
282 DEVELOPMENTAL REPRODUCTIVE TOXICOLOGY: A PRACTICAL APPROACH, SECOND EDITIONTotal of30/sex/groupSubset of10/sex/groupSubset of20/sex/groupAdditional6/sex/groupPND 4PND 7PND 21Cull to 4/sexBegin dosingWeanCull to 4/sexTK phlebotomy3/sex/groupPND 25Begin VP examPND 35Begin BPS examPND 62PND 63Motor activityStartle responseLearning and memoryEnd DosingClinical pathologyNecropsyHistologyMotor activityStartle responseLearning and memoryTK phlebotomy3/sex/groupPND 85LD 0LD 7PND 130Begin mating trialDams deliverNecropsy dams and pupsNecropsy paternal animalsAdministration PeriodFigure 8.7Within-litter study design. A robust within-litter design requires approximately 36 litters obtainedvia in-house mating or time-mated animals. VP, vaginal patency; BPS, balanopreputial separation.A specific type of adapted adult toxicity study design that has been proposed as an option forevaluating postnatal toxicity is the transgenerational protocol. This design has been proposed toevaluate effects of chemicals on the development of the reproductive system that may not otherwisebe detected by standard testing paradigms. This alternative design has been suggested because someendocrine-active chemicals were negative in standard multigeneration studies (likely because ofpostweaning selection of only one pup per sex per litter). 101 The dosing regimen for this transgenerationaldesign is in utero and lactational exposure (with the option of direct dosing of theoffspring), followed by necropsy of all offspring in adulthood. 102 The salient points to this designare that more offspring per litter are used (though fewer litters per group) and more endpointsrelated to endocrine-active compounds are evaluated. An important feature of this design is thatmultiple offspring per litter are examined following sexual maturity (since earlier examination may© 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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Prior to the early 1980s, numerous
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DEVELOPMENTAL AND REPRODUCTIVE TOXI
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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 80940003500Mean birth
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HUMAN STUDIES 811from monstrous, us
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HUMAN STUDIES 813A distinction is s
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CHAPTER 21Developmental and Reprodu
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