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

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432 DEVELOPMENTAL REPRODUCTIVE TOXICOLOGY: A PRACTICAL APPROACH, SECOND EDITIONF 0 PrematingMating Gestation Lactation0 DeliveryF 1 Postweaning Mating GestationLactationWeaningDeliveryF 0 PrematingMating GestationLactationF 2 Lactation0 DeliveryF 1 Postweaning Mating Gestation LactationTreatment PeriodStudy TaskNontreatment periodWeaningDeliveryEstrous smearsOffspring Development &Behavior TestingF 2b LactationFigure 10.4 Two-generation reproduction study schematics (OPPTS 870.3800 and OECD 416).Task 3, if required, is the crossover mating trial (no treatment required) that is performed todetermine whether the effects are couple-mediated or single-sex mediated.Task 4 is the F 1 generation test. Treatment with the test substance starts at weaning (PND 21),with each pup receiving the same treatment that the P 1 generation received. When 80 days of age,F 1 breeding pairs are cohabited for 1 week and separated when mating is confirmed. The F 1 femalecontinues on treatment and delivers its litter (F 2 ), and the adult F 1 and neonatal F 2 generationanimals are killed and necropsied.5. Developmental Neurotoxicity StudyThe developmental neurotoxicity study (OPPTS 870.6300 33 and OECD 426 34 ) design providesinformation for use in evaluating the potential for neurotoxic effects in offspring after exposure toa test substance in utero and/or via maternal milk or by direct dosing of the pup during the lactationperiod. Female rats are administered the test substance once daily beginning on GD 6 and continuingthrough PND 21. If there is no lactational transfer of the test substance or active metabolites, thendirect dosing of the pups beginning as early as PND 4 may be required. Female rats will be evaluatedfor adverse clinical signs observed during parturition, and for the duration of gestation, for littersize, live litter size, and pup viability at birth. F 1 generation males and females are tested as pupsand as adults for spontaneous locomotor activity, learning and memory, reflex development, andtime to sexual maturation. The functional observational battery (FOB) for pups and adults is© 2006 by Taylor & Francis Group, LLC
TESTING FOR REPRODUCTIVE TOXICITY 433Control*DL******Low***Medium******DL*High*Task 1Dose Range-FindingTask 2Continuous Breeding<strong>Ho</strong>lding RearingPeriod**Task 4<strong>Second</strong> Generation−6 0 15Weeks18 21 29 32Figure 10.5Reproductive assessment by continuous breeding schematic. See text for discussion of eachtask. The dark bars indicate treatment while the empty bars indicate no treatment. The twoseparate bars indicate single housing while the thicker bar indicates cohousing. The descendingarrows indicate the birth of a litter. DL, dominant lethal; *, limited necropsy; ** full necropsy.(Adapted from Chapin and Sloan, Environ. Health Perspect., 105(Suppl 1), 199, 1997.)performed at specified intervals. Neurohistopathological examination and morphometry are performedon selected brain regions (see Figure 10.6).6. Combined Repeated Dose Toxicity Study with the Reproductionand Developmental Toxicity Screening TestThe combined repeated dose toxicity study with the reproduction and developmental toxicityscreening test (OECD 422 20 and OPPTS 870.3650 35 ) is being required in the testing program ofhigh production volume (HPV) chemicals. HPV chemicals are those chemicals that are producedin or imported to the United States in amounts over 1 million pounds per year. The Chemical Rightto-KnowInitiative (1998) is the response to an EPA study that found that very little basic toxicityinformation is publicly available on most of the HPV commercial chemicals made and used in theUnited States. For further information concerning this program, go to http://www.epa.gov/opptintr/chemrtk/sidsappb.htm. This study design provides limited information on systemic toxicity andneurotoxicity following repeated treatments. It provides initial information on possible effects onmale and female reproductive performance, such as gonadal function, mating behavior, conception,development of the conceptus, and parturition. It is not an alternative to, nor does it replace, theexisting guidelines in OPPTS 870.3700, OPPTS 870.3800, OPPTS 870.6200, and OPPTS 870.7800,or the equivalent OECD studies. This study cannot be used as a definitive study for the setting ofa developmental or reproductive NOAEL.Males are treated for a minimum of 4 weeks (2 weeks precohabitation, during the mating period,and routinely 2 weeks postmating). Females are treated for 2 weeks precohabitation, during the© 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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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 80940003500Mean birth
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HUMAN STUDIES 811from monstrous, us
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HUMAN STUDIES 815G. Childhood Cance
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HUMAN STUDIES 829B. The Formation o
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HUMAN STUDIES 837with spina bifida
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HUMAN STUDIES 83926. Haglund, B. an
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CHAPTER 21Developmental and Reprodu
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