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

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386 DEVELOPMENTAL REPRODUCTIVE TOXICOLOGY: A PRACTICAL APPROACH, SECOND EDITIONTable 9.34Endpoints of reproductive toxicity studiesApproximate Chronological Order of CollectionEstrous cyclicityPrecoital intervalSexual behaviorMating/fertility indices and reproductive outcomeDuration of gestationParturitionNeonatal survival indicesPrenatal mortalityNesting and nursing behaviorAssessment of sperm qualityWeight and morphology (macroscopic andmicroscopic) of reproductive organsOocyte quantificationQualitative and quantitative physiologic endpointsrevealing unique toxicities of pregnancy andlactationViable litter size/live birth indexSex ratio in progenyNeonatal growthLandmarks of sexual maturityFunctional toxicities and CNS maturationLearning and memoryRanked by SensitivityViable litter size/live birth indexNeonatal growth aNeonatal survival indicesPrenatal mortalityAssessment of sperm qualityWeight and morphology (macroscopic and microscopic)of reproductive organsEstrous cyclicityPrecoital intervalMating and fertility indices and reproductiveoutcomeDuration of gestationParturitionLandmarks of sexual maturityFunctional toxicities and CNS maturationLearning and memoryQualitative and quantitative physiologic endpointsrevealing unique toxicities of pregnancy and lactationNesting and nursing behaviorSexual behaviorSex ratio in progenyOocyte quantificationaBolded endpoints may be assessed and/or appropriate for evaluation in humans.Because sensitivity of an endpoint may be methodologically or biologically dependent, theranking in Table 9.34 is relatively arbitrary and should not be considered a definitive ranking ofendpoints. Mode of action may determine which measure is more sensitive.1. Viable Litter Size/Live Birth IndexThe calculation of live litter size and live birth index is as follows:Live litter size =Live birth index =Total viable pups on day 0Number litters with viable pups on day 0Number of live offspringNumber live offspring delivered × 100As an apical measure, viable litter size is frequently the most sensitive indicator of reproductivetoxicity and is a very stable index. Decreased numbers in this endpoint relative to the concurrentcontrol group can result from a reduction in the ovulatory rate and timing, from shifts in the timingof tubal transport, and from reductions in implantation rate, postimplantation survival, or spermparameters (motility or concentration). In assessing the number of viable pups, it is important toexamine the litters as soon as possible following birth to ascertain the number of live pups versusthe number of stillborn pups. In addition, cannibalism of the progeny by the dam may result in aninaccurate determination of the number of pups born. However, this concern has probably beenoverstated as a technical problem except in instances where offspring are born dead or malformed,or there is a specific effect on CNS function by the test agent. Problems with cannibalism havedecreased because of improvements in husbandry and laboratory practices, coupled with betterdefinedstocks of animals. Optimal offspring quantification can be accomplished by examining thedam at least twice each day (in the morning and afternoon) during the period of expected parturition(beginning on GD 21). These frequent examinations are necessary to detect dystocia. Within the© 2006 by Taylor & Francis Group, LLC
DEVELOPMENTAL AND REPRODUCTIVE TOXICITY STUDY FINDINGS 387authors’ laboratory, the historical control mean live litter size for Crl:CD ® (SD)IGS BR rats is 14.1pups per litter. When sufficient numbers of animals are included in the study to produce approximately20 litters per group, compound-treated group mean reductions of as little as one pup perlitter may be an indicator of an adverse effect. Decrements of 1.5 pups per litter and greater arestrong signals of reproductive toxicity. This is especially true if differences from the control groupoccur in a dose-related manner.2. Neonatal GrowthA change in neonatal growth compared to the concurrent control is another endpoint that oftenindicates toxicity in a reproductive toxicity study. Adverse effects can be manifested by reducedbirth weights caused by growth retardation in utero and/or by reduced body weight gain followingbirth. Reductions in body weight gain following birth may be a result of indirect exposure to thetest article through nursing or may be attributable to decreased milk production by the dam. Groupmean male pup birth weights are generally approximately 0.5 g greater than group mean femalebirth weights. It is of critical importance to evaluate the neonatal growth curve in conjunction withlitter size to control for the confounding effects of within-litter competition. This can be accomplishedby using a nested analysis of variance, in which the covariate is live litter size. 56 Meanabsolute pup body weight differences of 10% or more will typically result in statistical significance.In studies that use the dietary route of exposure, reductions in offspring body weight that areobserved only during the week prior to weaning (postnatal days [PND] 14 to 21) are most likelya result of direct consumption of the feed by the pups. In a study using a fixed concentration ofthe test article in the diet, the milligram per kilogram exposure of these pups during the week priorto weaning and immediately following weaning is often much greater than that of the dam. Thisis because of the higher proportional consumption of food by the pups. It is also important toconsider route of exposure when comparing pup body weights with historical control data. Forexample, in the typical EPA multigeneration study design via whole-body inhalation, the dams areremoved from the pups and are exposed to the test material for 6 h/d. Because of this separationfrom the litter, pup body weights at weaning on PND 21 are generally approximately 20% lessthan the weights of pups from a study employing an oral (dietary, gavage, or drinking water) routeof exposure.3. Neonatal Survival IndicesNeonatal survival indices, in conjunction with offspring body weights, are used to gauge disturbancesin postnatal salubrity, growth, and development. When evaluating postnatal survival, it isimportant to maintain the litter as the experimental unit. However, it is also useful to inspect theabsolute numbers of deaths in each group. Standardization of litter size is an option in all guidelines.The United States convention is to standardize litters on PND 4, while litter standardization is oftennot performed in Europe. Neither approach is clearly right or wrong. The main advantage of littersize standardization is reduction of the variance in offspring weight due to litter size differences.This approach will improve sensitivity and make the historical control data range less variable.However, using this approach can decrease the likelihood of identifying outlier pup growth, becausesome pups are randomly euthanized. Assuming that litters are standardized on PND 4 (e.g., to 8or 10 pups), the method for calculating the mean litter proportion of postnatal survival is as follows:Postnatal survival between birth andPND 0 or PND 4 (prior to selection)(% per litter)=Σ(Viable pups per litter on PND 0or PND 4/No. pups born per litter)Number litters per group× 100© 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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Table 6.10DescriptionMuscular Syste
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Distalphalanges offingersseparatedF
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Table 6.11DescriptionIntermediateme
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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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CHAPTER 9Significance, Reliability,
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Prior to the early 1980s, numerous
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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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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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CHAPTER 21Developmental and Reprodu
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