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

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NONCLINICAL JUVENILE TOXICITY TESTING 307Table 8.9 Example of developmental delay in surface righting reflexSex Control T1 T2 T3A. Total Number of Pups Available for AssessmentMales 5.1 ± 0.10 5.0 ± 0.08 5.1 ± 0.13 5.1 ± 0.19Females 5.1 ± 0.15 5.1 ± 0.17 5.1 ± 0.19 5.2 ± 0.27Combined 5.1 ± 0.10 5.1 ± 0.11 5.1 ± 0.14 5.2 ± 0.18B. % Positively Responding (Number of Pups)MalesTotal pups 95 119 100 108PND 5 95% (90) 98% (117) 94% (94) 85% (92)PND 6 100% (95) 100% (119) 100% (100) 100% (108)FemalesTotal Pups 108 112 110 102PND 5 86% (93) 89% (100) 88% (97) 78% (80)PND 6 100% (108) 99% (111) 100% (110) 98% (100)PND 7 100% (112) 100% (102)CombinedTotal Pups 203 231 210 210PND 5 90% (183) 94% (217) 91% (191) 82% (172)PND 6 100% (203) 100% (230) 100% (210) 99% (208)PND 7 100% (231) 100% (210)Notes: Surface righting response evaluated in Crl:CD ® (SD)IGS BR rat offspring,beginning on PND 5, with assessment continuing until positiveevidence of righting was observed (WIL Research Laboratories,LLC). The same data are presented in A and B. Section A presentsthe mean ± S.D. day of acquisition of surface righting for males,females, and combined sexes. Section B presents the percentage(total number) of rat offspring acquiring surface righting on eachday of assessment.The ICH guideline specifically mentions several preweaning developmental landmarks, includingpinna detachment, hair growth, and incisor eruption, and notes that these measures are highlycorrelated with body weight and postcoital age, especially “when significant differences in gestationlength occur.” Moreover, functional developmental landmarks, such as surface and air righting,were also noted in the ICH guideline to be dependent on physical development. While a completediscussion of the many developmental landmarks is beyond the scope of this chapter, the authorshave chosen to address a few key evaluations, and we encourage the reader to review the extensiveliterature on this topic for more detail on specific evaluations.One commonly evaluated landmark of functional development is surface righting. The surfacerightingreflex evaluates the ability of the animal to regain a normal upright stance when placed ina supine position on a flat surface. 132 This reflex is present soon after birth in rats, although thetime required to attain an upright stance decreases as the animal ages. 133 At the authors’ facility,this test is performed beginning on PND 5 (one day after litter standardization) for the rat, with a15-s window for test completion. Neonates with negative responses (no observed righting) areevaluated on sequential days until a positive response is noted. Under these testing conditions, theapproximate average age at which righting occurs is PND 5. Because the age at onset of testingequals the age at which a positive response is observed, a delay in acquisition of this landmark ismost easily noted as an increase in the number of animals (on a litter basis) with a negative responseon the first day of testing. An example of such a delay is provided in Table 8.9. Although not© 2006 by Taylor & Francis Group, LLC
308 DEVELOPMENTAL REPRODUCTIVE TOXICOLOGY: A PRACTICAL APPROACH, SECOND EDITIONevident in this example, it is important to note that a statistical difference from control in the meanage at acquisition for this test is a key indicator of a test article–related change and should not beignored.Hair growth, incisor eruption, and eyelid separation are well accepted landmarks of physicaldevelopment, and both incisor eruption and eyelid separation were required endpoints of analysisin the CBTS. 105 For each of these tests, the neonate is evaluated from the first day of testing untila positive response is noted. Of course, evaluation of the acquisition of some landmarks is notpossible in species with such long gestational lengths that they are typically born with hair (dog,pig) or with separated eyelids (pig).Habituation is another functional reflex that is often assessed in a variety of study designs.Habituation is the progressive decrease in response to repeated stimulation that cannot be attributedto receptor fatigue or adaptation. 134 Glass and Singer characterized habituation as the most importantmechanism by which humans adapt and survive in modern society. 135 It is ubiquitous in nature andmost multicellular organisms have been shown to exhibit some form of habituation. 136 The regulatoryagencies consider development of the habituation response to be a key endpoint for evaluation.56,129 Habituation can also be used as a measure of basic learning, and in the CBTS, it wasdetermined to be a consistent method for detecting toxicity caused by methyl mercuric chloride. 104This reflex can be evaluated with a number of automated functional tests, such as the auditorystartle habituation test and the locomotor activity test. More detailed information on this reflex isprovided below as part of the discussion of each behavior.As Lochry pointed out in her review, landmarks of physical and functional development areoften highly correlated with body weight. 130 Therefore, when test article–related changes in landmarksof physical and functional development are observed, correlative changes in behavioralassessments may be noted as well. For example, delays in the acquisition of physical landmarkscan indicate a general developmental delay that may influence the normal ontogeny of locomotoractivity or the habituation to a startle stimulus. It is also critical to note that preweaning developmentallandmarks may be affected by maternal behavior. If the mother becomes incapable ofadequately rearing her young, growth of the offspring will be negatively impacted. This detrimentalmaternal influence can profoundly affect the offspring, should be carefully monitored during thecourse of the study, and must be considered during evaluation of the data.b. Landmarks of Sexual DevelopmentTwo additional standard landmarks of sexual development that are included in both juvenile andadult reproduction studies are balanopreputial separation and vaginal patency (see Chapters 9 and10 for descriptions). These landmarks are acquired by males or females, respectively, prior to theonset of puberty and are triggered by the presence of reproductive hormones. 137Evaluation of balanopreputial separation is typically conducted daily until there is evidencethat the prepuce has separated from the glans penis. 138 There is some thought that preputialseparation can be accelerated by repeated examinations; however, to ensure that the day of acquisitionis not overlooked, many laboratories will begin the examinations between PND 35 to 40 inthe rat. 137 In the authors’ laboratory, the mean age at acquisition of balanopreputial separation inthe Crl:CD ® (SD)IGS BR rat is approximately PND 45. The authors have also developed limiteddata in the New Zealand White rabbit, which indicate that balanopreputial separation is achievedon approximately PND 72. In addition, data developed at the authors’ laboratory in the beagle dogreveal that the mean age at acquisition of balanopreputial separation is approximately PND 51 (seeTable 8.8). As with the other landmarks of development, delays and accelerations in the acquisitionof balanopreputial separation can occur. Acquisition is correlated with body weight, 139,140 but otherdetermining factors, such as the presence of reproductive hormone stimulation or endocrinemodulatingchemicals, including 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene, can also disruptnormal development. 141 Testes descent is another landmark of sexual development in the male that© 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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POSTNATAL DEVELOPMENTAL MILESTONES
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PART IPrinciples and Mechanisms© 2
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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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Formation ofchoroid plexusof latera
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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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DEVELOPMENTAL AND REPRODUCTIVE TOXI
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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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y ESR spectrometry. 122 Further ESR
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CHAPTER 13Use of Toxicokinetics in
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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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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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CHAPTER 21Developmental and Reprodu
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